{"gene":"IL11","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":1993,"finding":"IL-11 and IL-6 share the common signal transducer gp130; anti-gp130 antibodies abolished IL-11-induced cell proliferation, protein tyrosine phosphorylation, and junB gene expression in TF-1 cells, whereas anti-IL-6R antibody had no effect on IL-11 signaling, demonstrating that IL-11 uses a distinct ligand-binding protein but the same gp130 signal transducer as IL-6.","method":"Anti-gp130 antibody neutralization, tyrosine phosphorylation assay, gene expression assay in TF-1 cells","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional readouts (proliferation, phosphorylation, gene expression), replicated across conditions, foundational mechanistic paper","pmids":["8360477"],"is_preprint":false},{"year":1995,"finding":"IL-11 activates JAK tyrosine kinases, MAP kinases, and pp90rsk; pp90rsk was identified as an H7-sensitive kinase critical for primary response gene (JunB, tis11, tis8) expression induced by IL-11; STAT91 tyrosine phosphorylation occurs but is not sufficient alone for primary response gene activation.","method":"Kinase activity assays, H7 inhibitor studies, gene expression analysis in mouse preadipocytes","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional kinase assays with pharmacological inhibitors, single lab, single paper","pmids":["7545369"],"is_preprint":false},{"year":1996,"finding":"The human IL-11 receptor alpha chain (IL-11Rα) absolutely requires gp130 for signaling; expression of IL-11Rα alone in Ba/F3 cells allowed IL-11 binding but no proliferative response, whereas co-expression of IL-11Rα with human gp130 generated high-affinity binding sites and IL-11-dependent proliferation.","method":"Molecular cloning, receptor transfection in Ba/F3 and M1 cells, radiolabeled IL-11 binding, proliferation assay, macrophage differentiation assay","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — receptor reconstitution with defined components plus multiple functional readouts, foundational receptor biology paper","pmids":["8637716"],"is_preprint":false},{"year":1994,"finding":"IL-1α and TGF-β (β1 and β2) are dose-dependent stimulators of IL-11 protein production, mRNA accumulation, and gene transcription in human lung fibroblasts, acting synergistically via largely PKC- and cyclic nucleotide-independent but partially calmodulin-dependent pathways; these regulation pathways are distinct from those governing IL-6.","method":"ELISA for IL-11 protein, Northern blot for mRNA, nuclear run-on for gene transcription, pharmacological inhibitors (HA1004, staurosporine, phorbol ester, W7, TFP, A23187)","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal methods (protein, mRNA, transcription) with defined pharmacological dissection of signaling pathways","pmids":["8133053"],"is_preprint":false},{"year":1997,"finding":"A soluble form of the IL-11 receptor alpha chain (sIL-11R) can signal in trans via gp130 (inducing gp130 phosphorylation, STAT3, and SHP-2 phosphorylation) but requires 10–20-fold higher IL-11 concentrations than membrane-bound receptor; sIL-11R can also act as an IL-11 antagonist by competing for limiting gp130 on cells expressing the transmembrane receptor.","method":"Recombinant protein expression, receptor binding assays (Kd measurements), phosphorylation assays, M1 differentiation assay, Ba/F3 proliferation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted soluble receptor signaling with quantitative binding and multiple functional assays, single lab","pmids":["9373251"],"is_preprint":false},{"year":2000,"finding":"IL-11 induces rapid tyrosine phosphorylation of gp130, STAT3 (at 0.1 ng/ml) and STAT1 (at 10 ng/ml), and phosphorylation of p42/p44 MAPKs in HUVECs; at low (STAT3/MAPK-activating) concentrations, IL-11 confers cytoprotection against immune-mediated injury in a protein synthesis- and MEK1-dependent manner without activating NF-κB.","method":"Western blot for phosphorylation, MEK inhibitor (PD98059), functional cytotoxicity assay with CTL and complement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling readouts plus functional cytoprotection assay with pharmacological inhibitor, single lab","pmids":["10725745"],"is_preprint":false},{"year":2003,"finding":"In human intestinal subepithelial myofibroblasts, IL-1β and TGF-β1 induce IL-11 secretion via AP-1 (c-Jun) activation and through ERK p42/44 and p38 MAPK pathways; p38 MAPK also mediates IL-11 mRNA stabilization; dominant-negative c-Jun adenovirus blocked IL-11 induction.","method":"EMSA for AP-1 binding, dominant-negative c-Jun adenovirus, MAP kinase inhibitors (SB-202190, PD-98059, U-0216), ELISA, Northern blot","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — dominant-negative genetic tool plus multiple pharmacological inhibitors and orthogonal molecular assays, single lab","pmids":["12760902"],"is_preprint":false},{"year":2004,"finding":"IL-11 protects human microvascular endothelium from alloinjury in vivo by upregulating survivin expression in endothelial cells and keratinocytes; topical survivin antisense oligonucleotide abrogated IL-11-mediated protection, identifying survivin induction as the cytoprotective mechanism.","method":"Human skin graft/SCID mouse alloinjury model, intradermal IL-11 injection, survivin antisense oligonucleotide, immunohistochemistry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with antisense knockdown of proposed mediator (survivin), single lab","pmids":["14734714"],"is_preprint":false},{"year":2005,"finding":"IL-11Rα (IL-11 receptor alpha) is required for IL-13-induced inflammation, fibrosis, hyaluronic acid accumulation, myofibroblast accumulation, alveolar remodeling, mucus metaplasia, and respiratory failure in mice; IL-13 stimulates CC chemokines, MMPs, mucin genes, and gob-5 via IL-11Rα-dependent pathways.","method":"IL-11Rα null mutant mice crossed to IL-13-overexpressing transgenic mice, histology, gene expression analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using null mutant mice with multiple orthogonal tissue phenotype readouts, establishes IL-11Rα as downstream effector of IL-13","pmids":["15699166"],"is_preprint":false},{"year":2008,"finding":"IL-11 promotes chronic gastric inflammation and associated tumorigenesis via excessive STAT3 and STAT1 activation; gp130(Y757F/Y757F) mice lacking IL-11Rα showed normal gastric STAT3 activation and failed to develop gastric tumors; reducing STAT3 activity (genetically or with antisense oligonucleotides) normalized gastric IL-11 expression.","method":"Genetic mouse models (gp130 mutant, IL-11Rα knockout, STAT3/STAT1 reduction), STAT3 antisense oligonucleotides, histology, immunohistochemistry","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models with reciprocal epistasis, multiple labs validated the gp130/STAT3/IL-11 axis","pmids":["18431520"],"is_preprint":false},{"year":2008,"finding":"Endogenous IL-11 signaling via IL-11Rα is required for antigen-induced Th2 eosinophilic inflammation, mucus production, and IL-13 production in the murine lung; an antagonistic IL-11 mutein reduced OVA-induced inflammation, mucus responses, and IL-13 production.","method":"IL-11Rα null mutant mice, OVA sensitization/challenge model, IL-11 mutein antagonist administration, BAL and lung analysis","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mutant combined with pharmacological antagonist, multiple readouts, single lab","pmids":["18617680"],"is_preprint":false},{"year":2009,"finding":"IL-17F induces IL-11 expression in bronchial epithelial cells via the Raf1-MEK1/2-ERK1/2-MSK1-CREB signaling pathway; siRNA knockdown of MSK1 inhibited CREB activation and IL-11 expression; Th2 cytokines (IL-4, IL-13) augmented this response.","method":"MEK inhibitors (PD-98059, U0126), Raf1 dominant-negative mutant overexpression, MSK1 inhibitors (Ro-31-8220, H89), MSK1 and CREB siRNA, phosphorylation assays","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — pharmacological inhibitors plus genetic dominant-negative and siRNA knockdown, multiple orthogonal approaches in single lab","pmids":["19251839"],"is_preprint":false},{"year":2009,"finding":"IL-11 signaling via IL-11Rα is required for uterine stromal decidualization; a PEGylated IL-11 antagonist administered to mice during early decidualization blocked IL-11 action in decidual cells (reducing cyclin D3 expression) and completely abolished pregnancy; IL-11 antagonist reduced STAT3 phosphorylation in human endometrial cells.","method":"In vivo PEGylated IL-11 antagonist administration in mice, immunohistochemistry for cyclin D3, STAT3 phosphorylation assay in HES cells","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological antagonist in vivo plus in vitro signaling assay, single lab","pmids":["19144959"],"is_preprint":false},{"year":2009,"finding":"IL-11 regulates autoimmune demyelination via immunoregulation (modulation of CD11c+ APC-mediated lymphocyte activation, reducing T effector cytokine production) and direct neuroprotection (reducing oligodendrocyte progenitor apoptosis and potentiating mitosis); IL-11Rα-null mice showed exacerbated EAE severity.","method":"IL-11Rα null mutant mice in EAE model, exogenous IL-11 treatment, T cell/APC co-culture cytokine assays, oligodendrocyte progenitor culture apoptosis/mitosis assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null mutant plus exogenous cytokine treatment with multiple cellular mechanistic readouts, single lab","pmids":["19734214"],"is_preprint":false},{"year":2011,"finding":"Mutations in IL11RA that render the receptor unable to mediate IL-11 signaling cause a human syndrome of craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth; cell-transfection experiments confirmed the p.Arg296Trp mutation causes loss of IL-11 signaling function.","method":"Homozygosity mapping, mutational analysis, cell transfection signaling assay, Il11ra null mouse phenotyping","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetics plus functional cell transfection validation plus mouse model, multiple independent families","pmids":["21741611"],"is_preprint":false},{"year":2013,"finding":"IL-11 is a hypoxia-inducible, VHL-regulated gene in human cancer cells; HIF-1 and AP-1 cooperatively mediate transcriptional activation of the IL-11 promoter; autocrine IL-11 production under hypoxia increases anchorage-independent growth via IL-11Rα-triggered STAT1-dependent signaling; IL-11 silencing abrogated hypoxia-induced tumor growth.","method":"Luciferase reporter assays for IL-11 promoter (HIF-1/AP-1 mutagenesis), siRNA knockdown of IL-11 and STAT1, VHL reconstitution, xenograft tumor models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — promoter mutagenesis/reporter assays plus genetic siRNA knockdown plus in vivo xenograft, single lab with multiple orthogonal methods","pmids":["23549086"],"is_preprint":false},{"year":2015,"finding":"IL-11 induces differentiation of CD11b+CD14+ monocytic myeloid-derived suppressor cells (MDSCs) from PBMCs via STAT3 phosphorylation through the IL-11Rα/gp130/JAK/STAT3 pathway; MDSC generated in the presence of IL-11 expressed higher arginase-1 and suppressed T cell proliferation.","method":"PBMC culture with IL-11, flow cytometry, STAT3 phosphorylation assay, T cell co-culture suppression assay","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional cell differentiation assay with signaling readout, single lab, single paper","pmids":["28781374"],"is_preprint":false},{"year":2016,"finding":"HMGA2 directly binds the IL-11 promoter and induces its transcriptional activity; IL-11 downstream of HMGA2 modulates cell migration and invasion through pSTAT3-dependent signaling in colorectal cancer cells.","method":"Chromatin immunoprecipitation-PCR, luciferase reporter assay, HMGA2 overexpression/silencing, invasion assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — ChIP and luciferase assays establish direct promoter binding, single lab","pmids":["26964871"],"is_preprint":false},{"year":2017,"finding":"IL-11 is the dominant TGFβ1-induced transcript in primary human fibroblasts and is required for TGFβ1's pro-fibrotic effect; IL-11 and IL-11Rα are expressed specifically in fibroblasts and drive non-canonical, ERK-dependent autocrine signaling required for fibrogenic protein synthesis; fibroblast-specific Il11 transgene expression or IL-11 injection causes heart and kidney fibrosis, while Il11ra1 deletion protects against fibrosis.","method":"Integrated imaging-genomics of human fibroblasts, fibroblast-specific transgenic mice, Il11ra1 knockout mice, ERK pathway assays, organ histology and function","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic mouse models (transgene, knockout) plus human fibroblast mechanistic studies with ERK pathway dissection, high-impact replicated findings","pmids":["29160304"],"is_preprint":false},{"year":2017,"finding":"Stromal/fibroblast loss of LKB1 induces IL-11 production and activation of the JAK/STAT3 pathway in tumor epithelia; JAK1/2 inhibitor ruxolitinib dramatically decreased polyposis in LKB1-deficient mice, placing IL-11-JAK/STAT3 downstream of LKB1 loss in gastrointestinal tumorigenesis.","method":"Mesenchymal Lkb1 conditional knockout mice, lineage tracing, immunohistochemistry, ruxolitinib treatment","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic conditional knockout with pharmacological epistasis validation and lineage tracing, single lab","pmids":["29202476"],"is_preprint":false},{"year":2018,"finding":"Autocrine JAK2 activation by IL-11 (via FRA1-mediated IL-11 expression induced by elevated ROS) mediates platinum drug resistance in ovarian cancer via JAK2-STAT5 signaling; JAK2 inhibitor or anti-IL-11 antibody overcomes resistance in vitro and in vivo.","method":"qHTCS screen, genomic sequencing, anti-IL-11 antibody, JAK2 inhibitor (LY2784544), in vitro and xenograft models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and antibody inhibition with in vitro and in vivo validation, single lab","pmids":["29662190"],"is_preprint":false},{"year":2020,"finding":"TGFβ1-induced IL-11 upregulation in fibroblasts drives pulmonary fibrosis via a TGF-β1/IL-11/MEK/ERK (TIME) signaling axis; anti-IL-11 antibody or MEK inhibitor PD98059 blocked senescence-associated collagen deposition; cytoplasmic p16INK4a accumulation in senescent fibroblasts upregulated MEK/ERK by inhibiting nuclear translocation of pERK1/2.","method":"Bmi-1 knockout mouse model, anti-IL-11 antibody, MEK inhibitor, p16INK4a/Bmi-1 double knockout, pulmonary fibroblast and AT2 cell culture","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mouse model plus pharmacological inhibition with multiple cellular readouts, single lab","pmids":["31959867"],"is_preprint":false},{"year":2020,"finding":"Fibroblast-specific IL-11Rα signaling drives chronic (but not acute) lung inflammation following bleomycin injury; conditional knockout of Il11ra1 in adult fibroblasts reduced ERK activation in fibroblasts and STAT3 phosphorylation in immune cells, and diminished NF-κB phosphorylation and pro-inflammatory gene activation.","method":"Fibroblast-specific Il11ra1 conditional knockout (loxP/Cre), bleomycin lung injury model, neutralizing anti-IL-11 antibodies, ERK/STAT3/NF-κB western blotting","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic deletion with pharmacological validation and multiple pathway readouts, single lab","pmids":["32656894"],"is_preprint":false},{"year":2021,"finding":"IL-11 drives fibrogenesis in fibroblasts through ERK/mTOR/P70RSK protein translation rather than STAT3; recombinant human IL-11 increases pSTAT3 in Il11ra1-null fibroblasts (indicating STAT3 activation by rhIL11 is IL-11Rα-independent); STAT3 inhibition causes ER stress and cell death; IL-11 selectively promotes Collagen 1 synthesis via an EPRS-regulated ribosome stalling mechanism; nintedanib causes dose-dependent ER stress.","method":"Il11ra1 null fibroblasts, ERK/mTOR/P70RSK inhibitors, STAT3 inhibitors, ER stress assays, ribosome stalling analysis, nintedanib/pirfenidone drug studies","journal":"Frontiers in molecular biosciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — null mutant cells plus multiple pharmacological inhibitors plus ribosome/translation mechanism dissection, single lab with multiple orthogonal methods","pmids":["34651016"],"is_preprint":false},{"year":2021,"finding":"IL-11 deletion (Il11-/-) places Il11 activity upstream of IL-6 in the bleomycin lung injury model; Il11-/- mice are protected from pulmonary fibrosis and show lesser ERK, STAT3, and NF-κB activation with reduced Il1b, Timp1, Ccl2 and IL-6 expression; unlike Il11ra1-/- mice, Il11-/- mice do not have craniosynostosis or long bone mass changes.","method":"Il11 knockout mice generation, bleomycin lung injury, ERK/STAT3/NF-κB assays, hematological profiling, bone phenotyping","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — novel knockout mouse with epistasis analysis and comparison to receptor knockout, multiple readouts, single lab","pmids":["34239012"],"is_preprint":false},{"year":2021,"finding":"IL-11 stimulates ERK activation leading to fibrogenesis in dermal fibroblasts independently of STAT3, TGFβ upregulation, and SMAD2/3 phosphorylation; TGFβ isoforms induce IL-11 secretion from dermal fibroblasts creating an autocrine loop; ERK inhibition phenocopied anti-IL-11 antibody in preventing TGFβ-induced HDF-to-myofibroblast transformation.","method":"IL-11 neutralizing antibody, IL11RA siRNA, ERK inhibitor, STAT3/SMAD2/3 western blotting, myofibroblast transformation assays, HDF cultures from SSc patients","journal":"Rheumatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — antibody, siRNA, and pharmacological inhibitor convergence on same phenotype with pathway dissection, single lab","pmids":["33590875"],"is_preprint":false},{"year":2021,"finding":"The MAFF-BACH1 heterodimer directly transcriptionally activates IL-11 expression (identified by ChIP-seq and RNA-seq), leading to STAT3 signaling activation; IL-11 inhibition suppresses tumor metastasis to similar levels as MAFF inhibition in breast cancer.","method":"ChIP-seq, RNA-seq, IL-11 inhibition, in vivo metastasis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — ChIP-seq identifies direct transcriptional target plus functional in vivo validation, single lab with multiple orthogonal approaches","pmids":["34262028"],"is_preprint":false},{"year":2021,"finding":"IL-11 stimulation of fibroblasts causes transient STAT3 phosphorylation and sustained ERK activation, triggering a proinflammatory transcriptional program including robust IL-33 upregulation (38-fold); STAT3 inhibition (but not MEK/ERK inhibition) prevented IL-11-induced IL33 expression; IL-11 stimulated a proinflammatory secretome including IL8, IL6, MCP1, CCL20, CXCL1/5/6.","method":"RNA sequencing time course, proteomic secretome analysis, STAT3 and MEK/ERK inhibitors, primary human kidney/lung/skin fibroblasts","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — RNA-seq plus proteomics plus pharmacological pathway dissection across multiple fibroblast types, single lab","pmids":["36012165"],"is_preprint":false},{"year":2021,"finding":"The rhomboid intramembrane protease RHBDL2 cleaves the IL-11 receptor between Ala-370 and Ser-371 in the extracellular domain (proximal to the plasma membrane), generating soluble IL-11R (sIL-11R) capable of IL-11 trans-signaling; RHBDL2 can cleave IL-11R within the early secretory pathway; the human mutation IL-11R-A370V prevents RHBDL2-mediated cleavage but does not impede classical IL-11 signaling.","method":"RHBDL2 overexpression, cleavage site mapping, transmembrane domain mutagenesis, IL-11 trans-signaling assays, subcellular localization studies","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct mutagenesis of cleavage site, functional trans-signaling validation, single lab with multiple mechanistic approaches","pmids":["33566379"],"is_preprint":false},{"year":2021,"finding":"Species-matched IL-11 is hepatotoxic rather than hepatoprotective; IL-11 secreted from APAP-damaged hepatocytes triggers an autocrine loop of NOX4-dependent cell death downstream of mitochondrial dysfunction; hepatocyte-specific deletion of Il11ra1 or germline deletion of Il11 protected against APAP-induced liver injury with reduced JNK and ERK activation.","method":"Hepatocyte-specific Il11ra1 conditional knockout, Il11 germline knockout, anti-IL-11RA neutralizing antibody, NOX4 pathway analysis, JNK/ERK western blotting, APAP liver injury model","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (tissue-specific and germline knockout) plus pharmacological intervention with mechanistic pathway dissection, single lab","pmids":["34108253"],"is_preprint":false},{"year":2021,"finding":"IL-11 suppresses host CD4+ T cell-mediated antitumor responses; adoptive bone marrow transfer and in vivo CD4+ T cell depletion showed the tumor-promoting activity of IL-11 is mediated through suppression of CD4+ T cells; IL11Rα-deficient CD4+ T cells showed elevated IFNγ and TNFα expression; IL-11 potently suppressed IFNγ, TNFα, IL-6, and IL-12p70 production by CD4+ T cells in vitro.","method":"Adoptive bone marrow transfer, in vivo T cell depletion, Il11ra conditional knockout, in vitro cytokine suppression assays, RNAscope, syngeneic tumor models","journal":"Cancer immunology research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with adoptive transfer epistasis plus in vitro mechanistic confirmation, single lab","pmids":["33906864"],"is_preprint":false},{"year":2021,"finding":"IL-11 stimulation of renal tubular epithelial cells (TECs) induces ERK- and p90RSK-mediated GSK3β inactivation, SNAI1 upregulation, and pro-inflammatory gene expression; TEC-specific deletion of Il11ra1 reduces pathogenic signaling and protects from renal injury-induced inflammation, fibrosis, and failure; anti-IL-11 therapy promotes TEC proliferation and parenchymal regeneration in chronic kidney disease.","method":"TEC-specific Il11ra1 conditional knockout, anti-IL-11 neutralizing antibody, ERK/p90RSK/GSK3β/SNAI1 pathway assays, acute and chronic kidney injury mouse models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic deletion with pharmacological validation and mechanistic signaling pathway dissection, single lab","pmids":["36470928"],"is_preprint":false},{"year":2022,"finding":"IL-11 stimulates an ERK/P90RSK axis that phosphorylates LKB1 at S325 and S428, causing LKB1 inactivation, which in turn inhibits AMPK and activates mTOR; this IL-11/ERK/LKB1/AMPK/mTOR axis drives myofibroblast transformation in stromal cells and mesenchymal transition in hepatocytes and epithelial cells; metformin-stimulated AMPK activation inhibits IL-11-induced phenotypes.","method":"Phospho-LKB1 site-specific analysis (S325, S428), AMPK/mTOR assays, metformin treatment, genetic manipulation of IL-11 in fatty liver disease mouse model, multiple cell types","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1 / Moderate — specific phosphorylation site identification plus genetic/pharmacological validation across multiple cell types and in vivo, single lab","pmids":["35992082"],"is_preprint":false},{"year":2022,"finding":"In Marfan syndrome aortic VSMCs, IL-11 is upregulated and drives ERK-dependent collagen secretion, MMP2/9 expression, aortic dilation, fibrosis, and inflammation; genetic deletion of Il11ra1 or therapeutic anti-IL11RA antibody (X209) reduced aortic pathology and ERK/COL1A1/MMP2/9 expression.","method":"Fbn1C1041G/+ Marfan mouse model, Il11-EGFP reporter, Il11ra1 knockout crossed to MFS mice, anti-IL11RA antibody X209, echocardiography, histology, immunoblotting","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reporter strain plus genetic double mutant plus pharmacological antibody with longitudinal imaging, single lab","pmids":["35135328"],"is_preprint":false},{"year":2022,"finding":"IL-11 activates pancreatic stellate cells (PSCs), which specifically express IL11RA in the pancreas, causing transient STAT3 phosphorylation and sustained ERK activation leading to PSC-to-myofibroblast transformation; IL-6 stimulation caused sustained STAT3 phosphorylation without ERK activation or PSC transformation; TGFβ, CTGF, and PDGF induced IL-11 secretion from PSCs via autocrine IL-11 activity; anti-IL11RA antibody prevented PSC activation.","method":"PSC culture with IL-11 vs IL-6, ERK/STAT3 assays, anti-IL11RA neutralizing antibody, pancreatic duct ligation mouse model, NF-κB signaling analysis","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct comparison IL-11 vs IL-6 signaling in PSCs with pharmacological neutralization plus in vivo model, single lab","pmids":["35408908"],"is_preprint":false},{"year":2023,"finding":"IL-11 in monocytes induces NLRP3 inflammasome activation (upregulating NFKB1, NLRP3, IL1B by scRNA-seq); IL-11R+ monocytes in CSF of MS patients upregulate NLRP3 inflammasome genes, complement, IL-18, and migratory genes (VEGFA/B); anti-IL-11 mAb in EAE mice decreased NFκBp65+, NLRP3+, and IL-1β+ monocytes in the CNS.","method":"Single-cell RNA sequencing of IL-11-stimulated PBMCs, IL-11R+-sorted CSF cells, anti-IL-11 mAb treatment in EAE mice","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 / Strong — scRNA-seq mechanistic readouts plus in vivo antibody treatment in disease model, single lab with multiple orthogonal methods","pmids":["37339207"],"is_preprint":false},{"year":2023,"finding":"IL-11-induced renal tubular epithelial cell EMT is dependent on sequential activation of STAT3 and ERK1/2 signaling and upregulation of metadherin (MTDH); micheliolide (MCL) competitively inhibits IL-11 binding to IL-11Rα1, suppressing STAT3/ERK1/2-metadherin pathways and inhibiting IL-11-induced EMT and fibrosis.","method":"IL-11 stimulation of RTECs, STAT3/ERK inhibitors, MCL competitive binding assay, UUO mouse model, dimethylaminomicheliolide (DMAMCL) in vivo","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibitor studies in vitro plus in vivo model, competitive binding mechanism proposed with in vitro support, single lab","pmids":["37673330"],"is_preprint":false},{"year":2024,"finding":"As mice age, IL-11 upregulates across tissues to regulate an ERK-AMPK-mTORC1 axis governing cellular and organismal aging pathologies; deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity, and frailty; anti-IL-11 treatment of aged mice improves metabolism and muscle function; genetic deletion of Il11 extended lifespan by 24.9% on average.","method":"Il11 and Il11ra1 knockout mice, anti-IL-11 antibody administration from 75 weeks, ERK/AMPK/mTORC1 pathway assays, lifespan studies in both sexes","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models plus pharmacological treatment with lifespan and pathway endpoints, replicated across sexes, single lab","pmids":["39020175"],"is_preprint":false},{"year":2024,"finding":"ALKBH5-mediated m6A demethylation of IL-11 mRNA increases IL-11 mRNA stability and protein levels in cardiac macrophages, driving macrophage-to-myofibroblast transition (MMT) under hypertensive stress; macrophage-specific ALKBH5 knockout inhibited MMT and cardiac fibrosis; IL-11 overexpression in macrophages reversed the ALKBH5-deficient phenotype.","method":"RNA immunoprecipitation sequencing, macrophage-specific ALKBH5 knockout, lineage tracing, parabiosis, single-cell transcriptomics, siRNA targeting ALKBH5 and IL11RA1 in monocytes","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — RIP-seq identifies direct m6A target, genetic knockout with rescue experiment, multiple orthogonal approaches, single lab","pmids":["38443404"],"is_preprint":false},{"year":2024,"finding":"IL-11 functions as a ligand of EGFR in brain metastasis from EGFR-mutated NSCLC; IL-11 secreted from reactive astrocytes binds EGFR on tumor cells activating downstream signaling to upregulate PDL1 and promote CD8+ T cell apoptosis; IL-11 also signals via its canonical IL-11Rα/gp130 receptor; combined gp130 and EGFR inhibition suppressed brain metastasis growth.","method":"Co-culture of astrocytes and tumor cells, EGFR binding/activation assays, PDL1 expression analysis, in vivo brain metastasis models, gp130 and EGFR inhibitors","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual receptor pathway (EGFR and gp130) identified with pharmacological inhibition and in vivo validation, single lab; EGFR as IL-11 receptor is a novel and not yet independently replicated claim","pmids":["38696655"],"is_preprint":false},{"year":2016,"finding":"IL-11R1 (but not IL-11R2 or IL-6R) promotes transcytosis of IL-11 across polarized epithelial cell barriers; basolaterally supplied IL-11 is transported to the apical side in an IL-11R1-dependent, intracellular domain-dependent manner; synthetic transfer of the IL-11R1 intracellular domain to IL-6R confers transcytotic activity on IL-6.","method":"Polarized cell transcytosis assays, domain swap experiments (IL-11R1 intracellular domain transferred to IL-6R), comparison of IL-11R1 vs IL-11R2 vs IL-6R","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — domain swap mutagenesis plus functional transcytosis assay with receptor specificity controls, single lab","pmids":["27425614"],"is_preprint":false},{"year":2020,"finding":"A homozygous variant in IL6ST (p.R281Q/p.R279Q in mice) causes selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling; this selectivity phenocopies aspects of IL-11Rα deficiency (craniosynostosis, teeth abnormalities, reduced litter size).","method":"In vitro transfected cell line signaling assays, primary patient-derived cells, genome-edited mouse model (Il6st p.R279Q)","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 1 / Strong — human genetics with functional in vitro validation plus corresponding mouse genome-edited model, demonstrates structural specificity of GP130 for IL-11 signaling","pmids":["32566365"],"is_preprint":false},{"year":2021,"finding":"piR-2158 acts as a transcriptional repressor of IL-11 by competing with AP-1 transcription factor subunit FOSL1 to bind the IL-11 promoter; STAT3 signaling mediates piR-2158-IL-11 regulation of cancer cell stemness, tumor growth, and angiogenesis in breast cancer.","method":"RNA-seq, ChIP-seq, luciferase reporter assays, FOSL1 competition assays, STAT3 signaling assays","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — ChIP-seq and luciferase assays for promoter competition, single lab, novel mechanism not independently replicated","pmids":["37153732"],"is_preprint":false},{"year":2024,"finding":"Autocrine IL-11/IL-11RA signaling in docetaxel-resistant prostate cancer activates JAK1/STAT4 pathway; activated pSTAT4 translocates to the nucleus, binds CBP at the c-MYC promoter, and amplifies c-MYC transcription; disruption of IL-11/IL-11RA or JAK1/STAT4 reduces pSTAT4 nuclear binding to CBP and restores docetaxel sensitivity.","method":"Single-cell secretion profiling, ChIP-seq for pSTAT4, Co-IP of pSTAT4 and CBP, luciferase reporter assay, IL-11/IL-11RA inhibition in prostate cancer cells","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — ChIP-seq and Co-IP establish pSTAT4-CBP interaction at c-MYC promoter, single lab, single paper with novel JAK1/STAT4 pathway not yet replicated for IL-11","pmids":["38429845"],"is_preprint":false}],"current_model":"IL-11 is a fibroblast- and stromal-cell-enriched cytokine that signals through a heterodimeric IL-11Rα/gp130 receptor complex to drive non-canonical ERK/P90RSK/LKB1/AMPK/mTOR-dependent autocrine pro-fibrotic protein synthesis, while STAT3 phosphorylation is transient and context-dependent; TGFβ1 is the principal upstream inducer of IL-11 in fibroblasts; IL-11 also activates JAK/STAT3 in epithelial and immune cells to promote inflammation, NLRP3 inflammasome activity, and cancer progression; IL-11Rα undergoes ectodomain shedding by ADAM10 and RHBDL2 to generate soluble receptor capable of trans-signaling, and IL-11R1 promotes transcytosis of IL-11 across epithelial barriers; genetic deletion of Il11 or Il11ra1 is protective in models of cardiac, renal, pulmonary, and liver fibrosis and extends mammalian lifespan, establishing IL-11 as a central non-redundant driver of fibroinflammation and age-related pathology."},"narrative":{"mechanistic_narrative":"IL-11 is a stromal- and fibroblast-enriched member of the IL-6 cytokine family that drives fibroinflammation, tissue remodeling, and age-related pathology by signaling through a receptor complex in which a dedicated IL-11Rα ligand-binding chain partners with the shared signal transducer gp130 [PMID:8360477, PMID:8637716, PMID:32566365]. In fibroblasts and other mesenchymal cells, IL-11 is the dominant TGFβ1-induced transcript and is itself required for the pro-fibrotic effect of TGFβ1, establishing an autocrine loop that drives myofibroblast transformation and fibrogenic protein synthesis through non-canonical ERK signaling rather than STAT3 [PMID:29160304, PMID:33590875, PMID:35408908]. Mechanistically, IL-11 activates an ERK/P90RSK axis that inactivates LKB1 by phosphorylation at S325 and S428, thereby inhibiting AMPK and de-repressing mTOR to drive translational output, including EPRS-regulated, ribosome-stalling-dependent collagen synthesis [PMID:34651016, PMID:35992082]. In renal tubular epithelium this same ERK/p90RSK module inactivates GSK3β and upregulates SNAI1 to promote pro-inflammatory and EMT programs [PMID:36470928, PMID:37673330]. STAT3 phosphorylation downstream of IL-11 is transient and context-dependent in fibroblasts, but in epithelial, monocytic, and tumor cells IL-11 engages JAK/STAT3 to promote inflammation, NLRP3 inflammasome activation, myeloid suppressor differentiation, and cancer progression [PMID:18431520, PMID:28781374, PMID:36012165, PMID:37339207]. Genetic deletion of Il11 or Il11ra1, or anti-IL-11 therapy, protects against cardiac, pulmonary, renal, and hepatic fibrosis, suppresses tumor growth and metastasis, and extends mouse lifespan via an ERK-AMPK-mTORC1 aging axis, defining IL-11 as a non-redundant driver of fibrosis and aging [PMID:29160304, PMID:34239012, PMID:34108253, PMID:36470928, PMID:39020175]. IL-11Rα ectodomain shedding by the rhomboid protease RHBDL2 generates a soluble receptor capable of trans-signaling through gp130, and IL-11R1 additionally mediates transcytosis of IL-11 across polarized epithelial barriers [PMID:9373251, PMID:33566379, PMID:27425614]. Loss-of-function mutations in IL11RA, and a gp130 variant selectively abolishing IL-11 signaling, cause a human syndrome of craniosynostosis, maxillary hypoplasia, and dental anomalies [PMID:21741611, PMID:32566365].","teleology":[{"year":1993,"claim":"Established that IL-11, despite distinct ligand binding, converges on the shared gp130 transducer used by IL-6, defining the molecular basis of its signaling.","evidence":"Anti-gp130 vs anti-IL-6R antibody neutralization with proliferation, phosphorylation, and junB readouts in TF-1 cells","pmids":["8360477"],"confidence":"High","gaps":["Did not identify the IL-11-specific ligand-binding receptor chain","Downstream signaling branches not resolved"]},{"year":1996,"claim":"Identified IL-11Rα as the dedicated ligand-binding chain that obligately requires gp130 to assemble a functional high-affinity receptor.","evidence":"Receptor reconstitution by transfection of IL-11Rα +/- gp130 in Ba/F3 cells with radiolabeled binding and proliferation assays","pmids":["8637716"],"confidence":"High","gaps":["Receptor stoichiometry and structural architecture not defined","Downstream effectors not dissected"]},{"year":1995,"claim":"Resolved early intracellular branching, showing IL-11 activates JAK kinases, MAPKs, and pp90rsk, with pp90rsk—not STAT91 alone—critical for primary response gene induction.","evidence":"Kinase assays and H7 inhibitor studies with gene expression analysis in mouse preadipocytes","pmids":["7545369"],"confidence":"Medium","gaps":["Pharmacological inhibitor specificity limits causal assignment","Relative contribution of ERK vs STAT to phenotype unresolved"]},{"year":1994,"claim":"Defined upstream control of IL-11, showing IL-1α and TGFβ synergistically induce its transcription in lung fibroblasts via pathways distinct from IL-6 regulation.","evidence":"ELISA, Northern blot, nuclear run-on, and pharmacological dissection in human lung fibroblasts","pmids":["8133053"],"confidence":"High","gaps":["Transcription factors mediating induction not identified","Cell-type specificity of regulation not addressed"]},{"year":1997,"claim":"Demonstrated that a soluble IL-11Rα can signal in trans via gp130 but also act as an antagonist by sequestering limiting gp130, establishing dual modes of receptor function.","evidence":"Recombinant soluble receptor with Kd measurements, phosphorylation, and differentiation/proliferation assays","pmids":["9373251"],"confidence":"High","gaps":["Physiological source of soluble receptor not identified at this stage","In vivo relevance of trans-signaling not tested"]},{"year":2000,"claim":"Showed concentration-dependent signaling output, with low-dose IL-11 conferring STAT3/MAPK- and protein-synthesis-dependent cytoprotection without NF-κB activation.","evidence":"Phosphorylation Western blots, MEK inhibitor PD98059, and CTL/complement cytotoxicity assays in HUVECs","pmids":["10725745"],"confidence":"Medium","gaps":["Downstream cytoprotective effectors not yet identified","Single endothelial system"]},{"year":2004,"claim":"Identified survivin induction as a concrete cytoprotective effector of IL-11 in endothelium in vivo.","evidence":"Human skin graft/SCID alloinjury model with survivin antisense oligonucleotide and immunohistochemistry","pmids":["14734714"],"confidence":"Medium","gaps":["Signaling link from receptor to survivin not mapped","Single antisense approach"]},{"year":2005,"claim":"Placed IL-11Rα as a required downstream effector of IL-13-driven airway inflammation, fibrosis, and remodeling, linking IL-11 to type 2 tissue pathology.","evidence":"IL-11Rα null mice crossed to IL-13 transgenics with histology and gene expression","pmids":["15699166"],"confidence":"High","gaps":["Cell type mediating IL-11Rα effects not defined","Signaling pathway downstream not dissected"]},{"year":2003,"claim":"Mapped the transcriptional machinery inducing IL-11, implicating AP-1/c-Jun and ERK/p38 MAPK with p38-dependent mRNA stabilization in myofibroblasts.","evidence":"EMSA, dominant-negative c-Jun adenovirus, MAPK inhibitors, ELISA, and Northern blot in intestinal myofibroblasts","pmids":["12760902"],"confidence":"High","gaps":["In vivo relevance of AP-1 control not tested","Did not link induced IL-11 to a phenotype"]},{"year":2008,"claim":"Established endogenous IL-11/IL-11Rα as required for type 2 airway inflammation and, separately, as a STAT3-driven promoter of gastric inflammation and tumorigenesis, revealing both inflammatory and oncogenic roles.","evidence":"IL-11Rα null mice with OVA challenge and IL-11 mutein antagonist; gp130/IL-11Rα/STAT genetic models with STAT3 antisense oligonucleotides","pmids":["18617680","18431520"],"confidence":"High","gaps":["Cell-type-specific source of pathogenic IL-11 not resolved","Mechanistic separation of STAT1 vs STAT3 contributions incomplete"]},{"year":2009,"claim":"Extended IL-11/IL-11Rα function across reproduction, neuroprotection, and additional MAPK-driven induction pathways, showing context-dependent protective and pathogenic roles.","evidence":"PEGylated IL-11 antagonist in decidualization; IL-11Rα null EAE model with neuroprotection assays; Raf/MEK/ERK/MSK1/CREB dissection of IL-17F-induced IL-11","pmids":["19144959","19734214","19251839"],"confidence":"High","gaps":["Tissue-specific receptor requirement not isolated genetically","Opposing protective vs pathogenic outcomes not mechanistically reconciled"]},{"year":2011,"claim":"Provided human genetic proof that loss of IL-11Rα-mediated signaling causes a developmental syndrome of craniosynostosis and dental anomalies.","evidence":"Homozygosity mapping, mutational analysis, transfection signaling assays, and Il11ra null mouse phenotyping","pmids":["21741611"],"confidence":"High","gaps":["Mechanism connecting IL-11 to suture and tooth biology not defined","Did not address fibrosis roles"]},{"year":2013,"claim":"Linked IL-11 to hypoxic tumor biology, showing HIF-1/AP-1-driven, VHL-regulated IL-11 supports autocrine STAT1-dependent anchorage-independent growth.","evidence":"Promoter reporter/mutagenesis, IL-11/STAT1 siRNA, VHL reconstitution, and xenograft models","pmids":["23549086"],"confidence":"High","gaps":["STAT1 vs STAT3 selectivity in this context not fully explained","Single tumor model"]},{"year":2016,"claim":"Revealed receptor-intrinsic transcytosis and identified additional transcriptional inducers, broadening IL-11 receptor functions beyond classical signaling.","evidence":"Polarized transcytosis assays with IL-11R1 intracellular domain swaps; HMGA2 ChIP-PCR and reporter assays in colorectal cancer","pmids":["27425614","26964871"],"confidence":"High","gaps":["Physiological cargo/role of transcytosis in vivo unclear","Trafficking machinery for transcytosis not identified"]},{"year":2017,"claim":"Reframed IL-11 as the dominant TGFβ1-induced, fibroblast-autocrine driver of fibrosis acting through non-canonical ERK signaling, and placed IL-11 downstream of stromal LKB1 loss in tumorigenesis.","evidence":"Imaging-genomics of human fibroblasts, fibroblast-specific transgenic and Il11ra1 knockout mice with ERK assays; mesenchymal Lkb1 conditional knockout with ruxolitinib","pmids":["29160304","29202476"],"confidence":"High","gaps":["Molecular steps from ERK to fibrogenic translation not yet detailed","Contribution of STAT3 not fully excluded across tissues"]},{"year":2018,"claim":"Demonstrated IL-11-driven autocrine JAK signaling underlies therapy resistance in cancer, expanding its oncogenic signaling repertoire.","evidence":"qHTCS screen, anti-IL-11 antibody, and JAK2 inhibitor in ovarian cancer in vitro and xenografts","pmids":["29662190"],"confidence":"Medium","gaps":["JAK2-STAT5 axis not validated genetically","Single cancer context"]},{"year":2020,"claim":"Defined cell-type-specific and senescence-linked fibrotic mechanisms and structurally established gp130's selectivity for IL-11 signaling.","evidence":"Fibroblast-specific Il11ra1 conditional knockout in bleomycin lung injury; Bmi-1/p16INK4a models of the TGFβ1/IL-11/MEK/ERK axis; IL6ST p.R279Q genome-edited mice and patient cells","pmids":["32656894","31959867","32566365"],"confidence":"High","gaps":["How fibroblast ERK signaling relays to immune STAT3/NF-κB not fully mapped","Structural basis of gp130 selectivity for IL-11 not resolved at atomic level"]},{"year":2021,"claim":"Consolidated the non-canonical ERK/mTOR translational mechanism of fibrogenesis, distinguished it from transient STAT3 signaling, identified RHBDL2-mediated soluble receptor generation, and expanded inflammatory/oncogenic roles including CD4+ T cell suppression and hepatotoxicity.","evidence":"Il11ra1-null fibroblasts with ERK/mTOR/P70RSK and EPRS ribosome-stalling analysis; RHBDL2 cleavage-site mutagenesis with trans-signaling assays; Il11 knockout and germline/hepatocyte-specific Il11ra1 models in lung and liver injury; CD4+ T cell adoptive transfer and depletion; MAFF-BACH1 and piR-2158 promoter studies","pmids":["34651016","33566379","34239012","34108253","33906864","33590875","36012165","34262028","37153732"],"confidence":"High","gaps":["Reconciliation of IL-11Rα-dependent vs -independent STAT3 activation incomplete","Relative in vivo weight of trans-signaling vs classical signaling unresolved"]},{"year":2022,"claim":"Identified the core IL-11/ERK/P90RSK/LKB1/AMPK/mTOR signaling axis and extended IL-11 fibrosis biology to vascular and pancreatic stromal disease.","evidence":"Phospho-LKB1 S325/S428 mapping with AMPK/mTOR and metformin studies; Fbn1 Marfan mouse with Il11ra1 knockout and anti-IL11RA antibody; PSC IL-11 vs IL-6 comparison with anti-IL11RA antibody","pmids":["35992082","35135328","35408908"],"confidence":"High","gaps":["Direct kinase responsible for LKB1 phosphorylation context not fully defined","Why ERK is sustained selectively by IL-11 vs IL-6 unresolved"]},{"year":2023,"claim":"Extended IL-11 to innate immune amplification via NLRP3 inflammasome activation in monocytes and detailed STAT3/ERK-dependent renal EMT, with druggable competitive inhibition.","evidence":"scRNA-seq of IL-11-stimulated PBMCs and MS CSF cells with anti-IL-11 mAb in EAE; RTEC STAT3/ERK-metadherin dissection with micheliolide competitive binding and UUO model","pmids":["37339207","37673330"],"confidence":"High","gaps":["Direct receptor-to-NLRP3 signaling steps not fully mapped","Micheliolide binding-site mechanism inferred indirectly"]},{"year":2024,"claim":"Established IL-11 as a driver of organismal aging via the ERK-AMPK-mTORC1 axis, and uncovered post-transcriptional (m6A) regulation and a non-canonical EGFR ligand role expanding its signaling biology.","evidence":"Il11/Il11ra1 knockout and anti-IL-11 lifespan/metabolic studies; ALKBH5 RIP-seq and macrophage-specific knockout with rescue; astrocyte IL-11/EGFR brain metastasis models; IL-11/JAK1/STAT4-CBP-c-MYC in prostate cancer","pmids":["39020175","38443404","38696655","38429845"],"confidence":"High","gaps":["EGFR-as-IL-11-receptor not independently replicated","JAK1/STAT4 pathway novel and not yet confirmed in other contexts"]},{"year":null,"claim":"It remains unresolved how IL-11 selectively sustains non-canonical ERK signaling versus transient STAT3, and what determines its opposing protective versus pathogenic outcomes across tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model explaining receptor-level bias toward ERK vs STAT3","Mechanistic basis for IL-11Rα-independent STAT3 activation by recombinant IL-11 unexplained","Physiological balance of classical vs trans- vs transcytotic signaling in vivo unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,18,32]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[3,18,34]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,28,40]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,18,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,24,31,37]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13,30,35]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[23,32]}],"complexes":["IL-11Rα/gp130 receptor complex"],"partners":["IL11RA","IL6ST","EGFR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P20809","full_name":"Interleukin-11","aliases":["Adipogenesis inhibitory factor","AGIF"],"length_aa":199,"mass_kda":21.4,"function":"Cytokine that stimulates the proliferation of hematopoietic stem cells and megakaryocyte progenitor cells and induces megakaryocyte maturation resulting in increased platelet production (PubMed:2145578). Also promotes the proliferation of hepatocytes in response to liver damage. Binding to its receptor formed by IL6ST and IL11RA activates a signaling cascade that promotes cell proliferation (PubMed:12919066). Signaling leads to the activation of intracellular protein kinases and the phosphorylation of STAT3. The interaction with the membrane-bound IL11RA and IL6ST stimulates 'classic signaling', whereas the binding of IL11 and soluble IL11RA to IL6ST stimulates 'trans-signaling' (PubMed:30279168)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P20809/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IL11","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/IL11","total_profiled":1310},"omim":[{"mim_id":"619752","title":"HYPER-IgE SYNDROME 4A, AUTOSOMAL DOMINANT, WITH RECURRENT INFECTIONS; HIES4A","url":"https://www.omim.org/entry/619752"},{"mim_id":"618523","title":"HYPER-IgE SYNDROME 4B, AUTOSOMAL RECESSIVE, WITH RECURRENT INFECTIONS; HIES4B","url":"https://www.omim.org/entry/618523"},{"mim_id":"617458","title":"PRKR-INTERACTING PROTEIN 1, IL11-INDUCIBLE; PRKRIP1","url":"https://www.omim.org/entry/617458"},{"mim_id":"616821","title":"THROMBOSPONDIN TYPE 1 DOMAIN-CONTAINING PROTEIN 1; THSD1","url":"https://www.omim.org/entry/616821"},{"mim_id":"616709","title":"ALPHA-1,4-N-ACETYLGLUCOSAMINYLTRANSFERASE; A4GNT","url":"https://www.omim.org/entry/616709"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":7.1}],"url":"https://www.proteinatlas.org/search/IL11"},"hgnc":{"alias_symbol":["IL-11","AGIF"],"prev_symbol":[]},"alphafold":{"accession":"P20809","domains":[{"cath_id":"1.20.1250.10","chopping":"34-65_78-152_161-196","consensus_level":"high","plddt":88.9862,"start":34,"end":196}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P20809","model_url":"https://alphafold.ebi.ac.uk/files/AF-P20809-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P20809-F1-predicted_aligned_error_v6.png","plddt_mean":82.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IL11","jax_strain_url":"https://www.jax.org/strain/search?query=IL11"},"sequence":{"accession":"P20809","fasta_url":"https://rest.uniprot.org/uniprotkb/P20809.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P20809/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P20809"}},"corpus_meta":[{"pmid":"29160304","id":"PMC_29160304","title":"IL-11 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IL-6.\",\n      \"method\": \"Anti-gp130 antibody neutralization, tyrosine phosphorylation assay, gene expression assay in TF-1 cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional readouts (proliferation, phosphorylation, gene expression), replicated across conditions, foundational mechanistic paper\",\n      \"pmids\": [\"8360477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"IL-11 activates JAK tyrosine kinases, MAP kinases, and pp90rsk; pp90rsk was identified as an H7-sensitive kinase critical for primary response gene (JunB, tis11, tis8) expression induced by IL-11; STAT91 tyrosine phosphorylation occurs but is not sufficient alone for primary response gene activation.\",\n      \"method\": \"Kinase activity assays, H7 inhibitor studies, gene expression analysis in mouse preadipocytes\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional kinase assays with pharmacological inhibitors, single lab, single paper\",\n      \"pmids\": [\"7545369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human IL-11 receptor alpha chain (IL-11Rα) absolutely requires gp130 for signaling; expression of IL-11Rα alone in Ba/F3 cells allowed IL-11 binding but no proliferative response, whereas co-expression of IL-11Rα with human gp130 generated high-affinity binding sites and IL-11-dependent proliferation.\",\n      \"method\": \"Molecular cloning, receptor transfection in Ba/F3 and M1 cells, radiolabeled IL-11 binding, proliferation assay, macrophage differentiation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — receptor reconstitution with defined components plus multiple functional readouts, foundational receptor biology paper\",\n      \"pmids\": [\"8637716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"IL-1α and TGF-β (β1 and β2) are dose-dependent stimulators of IL-11 protein production, mRNA accumulation, and gene transcription in human lung fibroblasts, acting synergistically via largely PKC- and cyclic nucleotide-independent but partially calmodulin-dependent pathways; these regulation pathways are distinct from those governing IL-6.\",\n      \"method\": \"ELISA for IL-11 protein, Northern blot for mRNA, nuclear run-on for gene transcription, pharmacological inhibitors (HA1004, staurosporine, phorbol ester, W7, TFP, A23187)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal methods (protein, mRNA, transcription) with defined pharmacological dissection of signaling pathways\",\n      \"pmids\": [\"8133053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"A soluble form of the IL-11 receptor alpha chain (sIL-11R) can signal in trans via gp130 (inducing gp130 phosphorylation, STAT3, and SHP-2 phosphorylation) but requires 10–20-fold higher IL-11 concentrations than membrane-bound receptor; sIL-11R can also act as an IL-11 antagonist by competing for limiting gp130 on cells expressing the transmembrane receptor.\",\n      \"method\": \"Recombinant protein expression, receptor binding assays (Kd measurements), phosphorylation assays, M1 differentiation assay, Ba/F3 proliferation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted soluble receptor signaling with quantitative binding and multiple functional assays, single lab\",\n      \"pmids\": [\"9373251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"IL-11 induces rapid tyrosine phosphorylation of gp130, STAT3 (at 0.1 ng/ml) and STAT1 (at 10 ng/ml), and phosphorylation of p42/p44 MAPKs in HUVECs; at low (STAT3/MAPK-activating) concentrations, IL-11 confers cytoprotection against immune-mediated injury in a protein synthesis- and MEK1-dependent manner without activating NF-κB.\",\n      \"method\": \"Western blot for phosphorylation, MEK inhibitor (PD98059), functional cytotoxicity assay with CTL and complement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling readouts plus functional cytoprotection assay with pharmacological inhibitor, single lab\",\n      \"pmids\": [\"10725745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In human intestinal subepithelial myofibroblasts, IL-1β and TGF-β1 induce IL-11 secretion via AP-1 (c-Jun) activation and through ERK p42/44 and p38 MAPK pathways; p38 MAPK also mediates IL-11 mRNA stabilization; dominant-negative c-Jun adenovirus blocked IL-11 induction.\",\n      \"method\": \"EMSA for AP-1 binding, dominant-negative c-Jun adenovirus, MAP kinase inhibitors (SB-202190, PD-98059, U-0216), ELISA, Northern blot\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — dominant-negative genetic tool plus multiple pharmacological inhibitors and orthogonal molecular assays, single lab\",\n      \"pmids\": [\"12760902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-11 protects human microvascular endothelium from alloinjury in vivo by upregulating survivin expression in endothelial cells and keratinocytes; topical survivin antisense oligonucleotide abrogated IL-11-mediated protection, identifying survivin induction as the cytoprotective mechanism.\",\n      \"method\": \"Human skin graft/SCID mouse alloinjury model, intradermal IL-11 injection, survivin antisense oligonucleotide, immunohistochemistry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with antisense knockdown of proposed mediator (survivin), single lab\",\n      \"pmids\": [\"14734714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IL-11Rα (IL-11 receptor alpha) is required for IL-13-induced inflammation, fibrosis, hyaluronic acid accumulation, myofibroblast accumulation, alveolar remodeling, mucus metaplasia, and respiratory failure in mice; IL-13 stimulates CC chemokines, MMPs, mucin genes, and gob-5 via IL-11Rα-dependent pathways.\",\n      \"method\": \"IL-11Rα null mutant mice crossed to IL-13-overexpressing transgenic mice, histology, gene expression analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using null mutant mice with multiple orthogonal tissue phenotype readouts, establishes IL-11Rα as downstream effector of IL-13\",\n      \"pmids\": [\"15699166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IL-11 promotes chronic gastric inflammation and associated tumorigenesis via excessive STAT3 and STAT1 activation; gp130(Y757F/Y757F) mice lacking IL-11Rα showed normal gastric STAT3 activation and failed to develop gastric tumors; reducing STAT3 activity (genetically or with antisense oligonucleotides) normalized gastric IL-11 expression.\",\n      \"method\": \"Genetic mouse models (gp130 mutant, IL-11Rα knockout, STAT3/STAT1 reduction), STAT3 antisense oligonucleotides, histology, immunohistochemistry\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models with reciprocal epistasis, multiple labs validated the gp130/STAT3/IL-11 axis\",\n      \"pmids\": [\"18431520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Endogenous IL-11 signaling via IL-11Rα is required for antigen-induced Th2 eosinophilic inflammation, mucus production, and IL-13 production in the murine lung; an antagonistic IL-11 mutein reduced OVA-induced inflammation, mucus responses, and IL-13 production.\",\n      \"method\": \"IL-11Rα null mutant mice, OVA sensitization/challenge model, IL-11 mutein antagonist administration, BAL and lung analysis\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mutant combined with pharmacological antagonist, multiple readouts, single lab\",\n      \"pmids\": [\"18617680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-17F induces IL-11 expression in bronchial epithelial cells via the Raf1-MEK1/2-ERK1/2-MSK1-CREB signaling pathway; siRNA knockdown of MSK1 inhibited CREB activation and IL-11 expression; Th2 cytokines (IL-4, IL-13) augmented this response.\",\n      \"method\": \"MEK inhibitors (PD-98059, U0126), Raf1 dominant-negative mutant overexpression, MSK1 inhibitors (Ro-31-8220, H89), MSK1 and CREB siRNA, phosphorylation assays\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — pharmacological inhibitors plus genetic dominant-negative and siRNA knockdown, multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"19251839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-11 signaling via IL-11Rα is required for uterine stromal decidualization; a PEGylated IL-11 antagonist administered to mice during early decidualization blocked IL-11 action in decidual cells (reducing cyclin D3 expression) and completely abolished pregnancy; IL-11 antagonist reduced STAT3 phosphorylation in human endometrial cells.\",\n      \"method\": \"In vivo PEGylated IL-11 antagonist administration in mice, immunohistochemistry for cyclin D3, STAT3 phosphorylation assay in HES cells\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological antagonist in vivo plus in vitro signaling assay, single lab\",\n      \"pmids\": [\"19144959\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-11 regulates autoimmune demyelination via immunoregulation (modulation of CD11c+ APC-mediated lymphocyte activation, reducing T effector cytokine production) and direct neuroprotection (reducing oligodendrocyte progenitor apoptosis and potentiating mitosis); IL-11Rα-null mice showed exacerbated EAE severity.\",\n      \"method\": \"IL-11Rα null mutant mice in EAE model, exogenous IL-11 treatment, T cell/APC co-culture cytokine assays, oligodendrocyte progenitor culture apoptosis/mitosis assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null mutant plus exogenous cytokine treatment with multiple cellular mechanistic readouts, single lab\",\n      \"pmids\": [\"19734214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mutations in IL11RA that render the receptor unable to mediate IL-11 signaling cause a human syndrome of craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth; cell-transfection experiments confirmed the p.Arg296Trp mutation causes loss of IL-11 signaling function.\",\n      \"method\": \"Homozygosity mapping, mutational analysis, cell transfection signaling assay, Il11ra null mouse phenotyping\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetics plus functional cell transfection validation plus mouse model, multiple independent families\",\n      \"pmids\": [\"21741611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL-11 is a hypoxia-inducible, VHL-regulated gene in human cancer cells; HIF-1 and AP-1 cooperatively mediate transcriptional activation of the IL-11 promoter; autocrine IL-11 production under hypoxia increases anchorage-independent growth via IL-11Rα-triggered STAT1-dependent signaling; IL-11 silencing abrogated hypoxia-induced tumor growth.\",\n      \"method\": \"Luciferase reporter assays for IL-11 promoter (HIF-1/AP-1 mutagenesis), siRNA knockdown of IL-11 and STAT1, VHL reconstitution, xenograft tumor models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — promoter mutagenesis/reporter assays plus genetic siRNA knockdown plus in vivo xenograft, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23549086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IL-11 induces differentiation of CD11b+CD14+ monocytic myeloid-derived suppressor cells (MDSCs) from PBMCs via STAT3 phosphorylation through the IL-11Rα/gp130/JAK/STAT3 pathway; MDSC generated in the presence of IL-11 expressed higher arginase-1 and suppressed T cell proliferation.\",\n      \"method\": \"PBMC culture with IL-11, flow cytometry, STAT3 phosphorylation assay, T cell co-culture suppression assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional cell differentiation assay with signaling readout, single lab, single paper\",\n      \"pmids\": [\"28781374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HMGA2 directly binds the IL-11 promoter and induces its transcriptional activity; IL-11 downstream of HMGA2 modulates cell migration and invasion through pSTAT3-dependent signaling in colorectal cancer cells.\",\n      \"method\": \"Chromatin immunoprecipitation-PCR, luciferase reporter assay, HMGA2 overexpression/silencing, invasion assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — ChIP and luciferase assays establish direct promoter binding, single lab\",\n      \"pmids\": [\"26964871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-11 is the dominant TGFβ1-induced transcript in primary human fibroblasts and is required for TGFβ1's pro-fibrotic effect; IL-11 and IL-11Rα are expressed specifically in fibroblasts and drive non-canonical, ERK-dependent autocrine signaling required for fibrogenic protein synthesis; fibroblast-specific Il11 transgene expression or IL-11 injection causes heart and kidney fibrosis, while Il11ra1 deletion protects against fibrosis.\",\n      \"method\": \"Integrated imaging-genomics of human fibroblasts, fibroblast-specific transgenic mice, Il11ra1 knockout mice, ERK pathway assays, organ histology and function\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic mouse models (transgene, knockout) plus human fibroblast mechanistic studies with ERK pathway dissection, high-impact replicated findings\",\n      \"pmids\": [\"29160304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Stromal/fibroblast loss of LKB1 induces IL-11 production and activation of the JAK/STAT3 pathway in tumor epithelia; JAK1/2 inhibitor ruxolitinib dramatically decreased polyposis in LKB1-deficient mice, placing IL-11-JAK/STAT3 downstream of LKB1 loss in gastrointestinal tumorigenesis.\",\n      \"method\": \"Mesenchymal Lkb1 conditional knockout mice, lineage tracing, immunohistochemistry, ruxolitinib treatment\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic conditional knockout with pharmacological epistasis validation and lineage tracing, single lab\",\n      \"pmids\": [\"29202476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Autocrine JAK2 activation by IL-11 (via FRA1-mediated IL-11 expression induced by elevated ROS) mediates platinum drug resistance in ovarian cancer via JAK2-STAT5 signaling; JAK2 inhibitor or anti-IL-11 antibody overcomes resistance in vitro and in vivo.\",\n      \"method\": \"qHTCS screen, genomic sequencing, anti-IL-11 antibody, JAK2 inhibitor (LY2784544), in vitro and xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and antibody inhibition with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"29662190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TGFβ1-induced IL-11 upregulation in fibroblasts drives pulmonary fibrosis via a TGF-β1/IL-11/MEK/ERK (TIME) signaling axis; anti-IL-11 antibody or MEK inhibitor PD98059 blocked senescence-associated collagen deposition; cytoplasmic p16INK4a accumulation in senescent fibroblasts upregulated MEK/ERK by inhibiting nuclear translocation of pERK1/2.\",\n      \"method\": \"Bmi-1 knockout mouse model, anti-IL-11 antibody, MEK inhibitor, p16INK4a/Bmi-1 double knockout, pulmonary fibroblast and AT2 cell culture\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mouse model plus pharmacological inhibition with multiple cellular readouts, single lab\",\n      \"pmids\": [\"31959867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fibroblast-specific IL-11Rα signaling drives chronic (but not acute) lung inflammation following bleomycin injury; conditional knockout of Il11ra1 in adult fibroblasts reduced ERK activation in fibroblasts and STAT3 phosphorylation in immune cells, and diminished NF-κB phosphorylation and pro-inflammatory gene activation.\",\n      \"method\": \"Fibroblast-specific Il11ra1 conditional knockout (loxP/Cre), bleomycin lung injury model, neutralizing anti-IL-11 antibodies, ERK/STAT3/NF-κB western blotting\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic deletion with pharmacological validation and multiple pathway readouts, single lab\",\n      \"pmids\": [\"32656894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 drives fibrogenesis in fibroblasts through ERK/mTOR/P70RSK protein translation rather than STAT3; recombinant human IL-11 increases pSTAT3 in Il11ra1-null fibroblasts (indicating STAT3 activation by rhIL11 is IL-11Rα-independent); STAT3 inhibition causes ER stress and cell death; IL-11 selectively promotes Collagen 1 synthesis via an EPRS-regulated ribosome stalling mechanism; nintedanib causes dose-dependent ER stress.\",\n      \"method\": \"Il11ra1 null fibroblasts, ERK/mTOR/P70RSK inhibitors, STAT3 inhibitors, ER stress assays, ribosome stalling analysis, nintedanib/pirfenidone drug studies\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — null mutant cells plus multiple pharmacological inhibitors plus ribosome/translation mechanism dissection, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34651016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 deletion (Il11-/-) places Il11 activity upstream of IL-6 in the bleomycin lung injury model; Il11-/- mice are protected from pulmonary fibrosis and show lesser ERK, STAT3, and NF-κB activation with reduced Il1b, Timp1, Ccl2 and IL-6 expression; unlike Il11ra1-/- mice, Il11-/- mice do not have craniosynostosis or long bone mass changes.\",\n      \"method\": \"Il11 knockout mice generation, bleomycin lung injury, ERK/STAT3/NF-κB assays, hematological profiling, bone phenotyping\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — novel knockout mouse with epistasis analysis and comparison to receptor knockout, multiple readouts, single lab\",\n      \"pmids\": [\"34239012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 stimulates ERK activation leading to fibrogenesis in dermal fibroblasts independently of STAT3, TGFβ upregulation, and SMAD2/3 phosphorylation; TGFβ isoforms induce IL-11 secretion from dermal fibroblasts creating an autocrine loop; ERK inhibition phenocopied anti-IL-11 antibody in preventing TGFβ-induced HDF-to-myofibroblast transformation.\",\n      \"method\": \"IL-11 neutralizing antibody, IL11RA siRNA, ERK inhibitor, STAT3/SMAD2/3 western blotting, myofibroblast transformation assays, HDF cultures from SSc patients\",\n      \"journal\": \"Rheumatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — antibody, siRNA, and pharmacological inhibitor convergence on same phenotype with pathway dissection, single lab\",\n      \"pmids\": [\"33590875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The MAFF-BACH1 heterodimer directly transcriptionally activates IL-11 expression (identified by ChIP-seq and RNA-seq), leading to STAT3 signaling activation; IL-11 inhibition suppresses tumor metastasis to similar levels as MAFF inhibition in breast cancer.\",\n      \"method\": \"ChIP-seq, RNA-seq, IL-11 inhibition, in vivo metastasis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP-seq identifies direct transcriptional target plus functional in vivo validation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"34262028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 stimulation of fibroblasts causes transient STAT3 phosphorylation and sustained ERK activation, triggering a proinflammatory transcriptional program including robust IL-33 upregulation (38-fold); STAT3 inhibition (but not MEK/ERK inhibition) prevented IL-11-induced IL33 expression; IL-11 stimulated a proinflammatory secretome including IL8, IL6, MCP1, CCL20, CXCL1/5/6.\",\n      \"method\": \"RNA sequencing time course, proteomic secretome analysis, STAT3 and MEK/ERK inhibitors, primary human kidney/lung/skin fibroblasts\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — RNA-seq plus proteomics plus pharmacological pathway dissection across multiple fibroblast types, single lab\",\n      \"pmids\": [\"36012165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The rhomboid intramembrane protease RHBDL2 cleaves the IL-11 receptor between Ala-370 and Ser-371 in the extracellular domain (proximal to the plasma membrane), generating soluble IL-11R (sIL-11R) capable of IL-11 trans-signaling; RHBDL2 can cleave IL-11R within the early secretory pathway; the human mutation IL-11R-A370V prevents RHBDL2-mediated cleavage but does not impede classical IL-11 signaling.\",\n      \"method\": \"RHBDL2 overexpression, cleavage site mapping, transmembrane domain mutagenesis, IL-11 trans-signaling assays, subcellular localization studies\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct mutagenesis of cleavage site, functional trans-signaling validation, single lab with multiple mechanistic approaches\",\n      \"pmids\": [\"33566379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Species-matched IL-11 is hepatotoxic rather than hepatoprotective; IL-11 secreted from APAP-damaged hepatocytes triggers an autocrine loop of NOX4-dependent cell death downstream of mitochondrial dysfunction; hepatocyte-specific deletion of Il11ra1 or germline deletion of Il11 protected against APAP-induced liver injury with reduced JNK and ERK activation.\",\n      \"method\": \"Hepatocyte-specific Il11ra1 conditional knockout, Il11 germline knockout, anti-IL-11RA neutralizing antibody, NOX4 pathway analysis, JNK/ERK western blotting, APAP liver injury model\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (tissue-specific and germline knockout) plus pharmacological intervention with mechanistic pathway dissection, single lab\",\n      \"pmids\": [\"34108253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 suppresses host CD4+ T cell-mediated antitumor responses; adoptive bone marrow transfer and in vivo CD4+ T cell depletion showed the tumor-promoting activity of IL-11 is mediated through suppression of CD4+ T cells; IL11Rα-deficient CD4+ T cells showed elevated IFNγ and TNFα expression; IL-11 potently suppressed IFNγ, TNFα, IL-6, and IL-12p70 production by CD4+ T cells in vitro.\",\n      \"method\": \"Adoptive bone marrow transfer, in vivo T cell depletion, Il11ra conditional knockout, in vitro cytokine suppression assays, RNAscope, syngeneic tumor models\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with adoptive transfer epistasis plus in vitro mechanistic confirmation, single lab\",\n      \"pmids\": [\"33906864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 stimulation of renal tubular epithelial cells (TECs) induces ERK- and p90RSK-mediated GSK3β inactivation, SNAI1 upregulation, and pro-inflammatory gene expression; TEC-specific deletion of Il11ra1 reduces pathogenic signaling and protects from renal injury-induced inflammation, fibrosis, and failure; anti-IL-11 therapy promotes TEC proliferation and parenchymal regeneration in chronic kidney disease.\",\n      \"method\": \"TEC-specific Il11ra1 conditional knockout, anti-IL-11 neutralizing antibody, ERK/p90RSK/GSK3β/SNAI1 pathway assays, acute and chronic kidney injury mouse models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic deletion with pharmacological validation and mechanistic signaling pathway dissection, single lab\",\n      \"pmids\": [\"36470928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-11 stimulates an ERK/P90RSK axis that phosphorylates LKB1 at S325 and S428, causing LKB1 inactivation, which in turn inhibits AMPK and activates mTOR; this IL-11/ERK/LKB1/AMPK/mTOR axis drives myofibroblast transformation in stromal cells and mesenchymal transition in hepatocytes and epithelial cells; metformin-stimulated AMPK activation inhibits IL-11-induced phenotypes.\",\n      \"method\": \"Phospho-LKB1 site-specific analysis (S325, S428), AMPK/mTOR assays, metformin treatment, genetic manipulation of IL-11 in fatty liver disease mouse model, multiple cell types\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — specific phosphorylation site identification plus genetic/pharmacological validation across multiple cell types and in vivo, single lab\",\n      \"pmids\": [\"35992082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Marfan syndrome aortic VSMCs, IL-11 is upregulated and drives ERK-dependent collagen secretion, MMP2/9 expression, aortic dilation, fibrosis, and inflammation; genetic deletion of Il11ra1 or therapeutic anti-IL11RA antibody (X209) reduced aortic pathology and ERK/COL1A1/MMP2/9 expression.\",\n      \"method\": \"Fbn1C1041G/+ Marfan mouse model, Il11-EGFP reporter, Il11ra1 knockout crossed to MFS mice, anti-IL11RA antibody X209, echocardiography, histology, immunoblotting\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reporter strain plus genetic double mutant plus pharmacological antibody with longitudinal imaging, single lab\",\n      \"pmids\": [\"35135328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-11 activates pancreatic stellate cells (PSCs), which specifically express IL11RA in the pancreas, causing transient STAT3 phosphorylation and sustained ERK activation leading to PSC-to-myofibroblast transformation; IL-6 stimulation caused sustained STAT3 phosphorylation without ERK activation or PSC transformation; TGFβ, CTGF, and PDGF induced IL-11 secretion from PSCs via autocrine IL-11 activity; anti-IL11RA antibody prevented PSC activation.\",\n      \"method\": \"PSC culture with IL-11 vs IL-6, ERK/STAT3 assays, anti-IL11RA neutralizing antibody, pancreatic duct ligation mouse model, NF-κB signaling analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct comparison IL-11 vs IL-6 signaling in PSCs with pharmacological neutralization plus in vivo model, single lab\",\n      \"pmids\": [\"35408908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-11 in monocytes induces NLRP3 inflammasome activation (upregulating NFKB1, NLRP3, IL1B by scRNA-seq); IL-11R+ monocytes in CSF of MS patients upregulate NLRP3 inflammasome genes, complement, IL-18, and migratory genes (VEGFA/B); anti-IL-11 mAb in EAE mice decreased NFκBp65+, NLRP3+, and IL-1β+ monocytes in the CNS.\",\n      \"method\": \"Single-cell RNA sequencing of IL-11-stimulated PBMCs, IL-11R+-sorted CSF cells, anti-IL-11 mAb treatment in EAE mice\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — scRNA-seq mechanistic readouts plus in vivo antibody treatment in disease model, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37339207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-11-induced renal tubular epithelial cell EMT is dependent on sequential activation of STAT3 and ERK1/2 signaling and upregulation of metadherin (MTDH); micheliolide (MCL) competitively inhibits IL-11 binding to IL-11Rα1, suppressing STAT3/ERK1/2-metadherin pathways and inhibiting IL-11-induced EMT and fibrosis.\",\n      \"method\": \"IL-11 stimulation of RTECs, STAT3/ERK inhibitors, MCL competitive binding assay, UUO mouse model, dimethylaminomicheliolide (DMAMCL) in vivo\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibitor studies in vitro plus in vivo model, competitive binding mechanism proposed with in vitro support, single lab\",\n      \"pmids\": [\"37673330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"As mice age, IL-11 upregulates across tissues to regulate an ERK-AMPK-mTORC1 axis governing cellular and organismal aging pathologies; deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity, and frailty; anti-IL-11 treatment of aged mice improves metabolism and muscle function; genetic deletion of Il11 extended lifespan by 24.9% on average.\",\n      \"method\": \"Il11 and Il11ra1 knockout mice, anti-IL-11 antibody administration from 75 weeks, ERK/AMPK/mTORC1 pathway assays, lifespan studies in both sexes\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models plus pharmacological treatment with lifespan and pathway endpoints, replicated across sexes, single lab\",\n      \"pmids\": [\"39020175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALKBH5-mediated m6A demethylation of IL-11 mRNA increases IL-11 mRNA stability and protein levels in cardiac macrophages, driving macrophage-to-myofibroblast transition (MMT) under hypertensive stress; macrophage-specific ALKBH5 knockout inhibited MMT and cardiac fibrosis; IL-11 overexpression in macrophages reversed the ALKBH5-deficient phenotype.\",\n      \"method\": \"RNA immunoprecipitation sequencing, macrophage-specific ALKBH5 knockout, lineage tracing, parabiosis, single-cell transcriptomics, siRNA targeting ALKBH5 and IL11RA1 in monocytes\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — RIP-seq identifies direct m6A target, genetic knockout with rescue experiment, multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"38443404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-11 functions as a ligand of EGFR in brain metastasis from EGFR-mutated NSCLC; IL-11 secreted from reactive astrocytes binds EGFR on tumor cells activating downstream signaling to upregulate PDL1 and promote CD8+ T cell apoptosis; IL-11 also signals via its canonical IL-11Rα/gp130 receptor; combined gp130 and EGFR inhibition suppressed brain metastasis growth.\",\n      \"method\": \"Co-culture of astrocytes and tumor cells, EGFR binding/activation assays, PDL1 expression analysis, in vivo brain metastasis models, gp130 and EGFR inhibitors\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual receptor pathway (EGFR and gp130) identified with pharmacological inhibition and in vivo validation, single lab; EGFR as IL-11 receptor is a novel and not yet independently replicated claim\",\n      \"pmids\": [\"38696655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IL-11R1 (but not IL-11R2 or IL-6R) promotes transcytosis of IL-11 across polarized epithelial cell barriers; basolaterally supplied IL-11 is transported to the apical side in an IL-11R1-dependent, intracellular domain-dependent manner; synthetic transfer of the IL-11R1 intracellular domain to IL-6R confers transcytotic activity on IL-6.\",\n      \"method\": \"Polarized cell transcytosis assays, domain swap experiments (IL-11R1 intracellular domain transferred to IL-6R), comparison of IL-11R1 vs IL-11R2 vs IL-6R\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — domain swap mutagenesis plus functional transcytosis assay with receptor specificity controls, single lab\",\n      \"pmids\": [\"27425614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A homozygous variant in IL6ST (p.R281Q/p.R279Q in mice) causes selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling; this selectivity phenocopies aspects of IL-11Rα deficiency (craniosynostosis, teeth abnormalities, reduced litter size).\",\n      \"method\": \"In vitro transfected cell line signaling assays, primary patient-derived cells, genome-edited mouse model (Il6st p.R279Q)\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — human genetics with functional in vitro validation plus corresponding mouse genome-edited model, demonstrates structural specificity of GP130 for IL-11 signaling\",\n      \"pmids\": [\"32566365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"piR-2158 acts as a transcriptional repressor of IL-11 by competing with AP-1 transcription factor subunit FOSL1 to bind the IL-11 promoter; STAT3 signaling mediates piR-2158-IL-11 regulation of cancer cell stemness, tumor growth, and angiogenesis in breast cancer.\",\n      \"method\": \"RNA-seq, ChIP-seq, luciferase reporter assays, FOSL1 competition assays, STAT3 signaling assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — ChIP-seq and luciferase assays for promoter competition, single lab, novel mechanism not independently replicated\",\n      \"pmids\": [\"37153732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Autocrine IL-11/IL-11RA signaling in docetaxel-resistant prostate cancer activates JAK1/STAT4 pathway; activated pSTAT4 translocates to the nucleus, binds CBP at the c-MYC promoter, and amplifies c-MYC transcription; disruption of IL-11/IL-11RA or JAK1/STAT4 reduces pSTAT4 nuclear binding to CBP and restores docetaxel sensitivity.\",\n      \"method\": \"Single-cell secretion profiling, ChIP-seq for pSTAT4, Co-IP of pSTAT4 and CBP, luciferase reporter assay, IL-11/IL-11RA inhibition in prostate cancer cells\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — ChIP-seq and Co-IP establish pSTAT4-CBP interaction at c-MYC promoter, single lab, single paper with novel JAK1/STAT4 pathway not yet replicated for IL-11\",\n      \"pmids\": [\"38429845\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-11 is a fibroblast- and stromal-cell-enriched cytokine that signals through a heterodimeric IL-11Rα/gp130 receptor complex to drive non-canonical ERK/P90RSK/LKB1/AMPK/mTOR-dependent autocrine pro-fibrotic protein synthesis, while STAT3 phosphorylation is transient and context-dependent; TGFβ1 is the principal upstream inducer of IL-11 in fibroblasts; IL-11 also activates JAK/STAT3 in epithelial and immune cells to promote inflammation, NLRP3 inflammasome activity, and cancer progression; IL-11Rα undergoes ectodomain shedding by ADAM10 and RHBDL2 to generate soluble receptor capable of trans-signaling, and IL-11R1 promotes transcytosis of IL-11 across epithelial barriers; genetic deletion of Il11 or Il11ra1 is protective in models of cardiac, renal, pulmonary, and liver fibrosis and extends mammalian lifespan, establishing IL-11 as a central non-redundant driver of fibroinflammation and age-related pathology.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL-11 is a stromal- and fibroblast-enriched member of the IL-6 cytokine family that drives fibroinflammation, tissue remodeling, and age-related pathology by signaling through a receptor complex in which a dedicated IL-11Rα ligand-binding chain partners with the shared signal transducer gp130 [#0, #2, #41]. In fibroblasts and other mesenchymal cells, IL-11 is the dominant TGFβ1-induced transcript and is itself required for the pro-fibrotic effect of TGFβ1, establishing an autocrine loop that drives myofibroblast transformation and fibrogenic protein synthesis through non-canonical ERK signaling rather than STAT3 [#18, #25, #34]. Mechanistically, IL-11 activates an ERK/P90RSK axis that inactivates LKB1 by phosphorylation at S325 and S428, thereby inhibiting AMPK and de-repressing mTOR to drive translational output, including EPRS-regulated, ribosome-stalling-dependent collagen synthesis [#23, #32]. In renal tubular epithelium this same ERK/p90RSK module inactivates GSK3β and upregulates SNAI1 to promote pro-inflammatory and EMT programs [#31, #36]. STAT3 phosphorylation downstream of IL-11 is transient and context-dependent in fibroblasts, but in epithelial, monocytic, and tumor cells IL-11 engages JAK/STAT3 to promote inflammation, NLRP3 inflammasome activation, myeloid suppressor differentiation, and cancer progression [#9, #16, #27, #35]. Genetic deletion of Il11 or Il11ra1, or anti-IL-11 therapy, protects against cardiac, pulmonary, renal, and hepatic fibrosis, suppresses tumor growth and metastasis, and extends mouse lifespan via an ERK-AMPK-mTORC1 aging axis, defining IL-11 as a non-redundant driver of fibrosis and aging [#18, #24, #29, #31, #37]. IL-11Rα ectodomain shedding by the rhomboid protease RHBDL2 generates a soluble receptor capable of trans-signaling through gp130, and IL-11R1 additionally mediates transcytosis of IL-11 across polarized epithelial barriers [#4, #28, #40]. Loss-of-function mutations in IL11RA, and a gp130 variant selectively abolishing IL-11 signaling, cause a human syndrome of craniosynostosis, maxillary hypoplasia, and dental anomalies [#14, #41].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established that IL-11, despite distinct ligand binding, converges on the shared gp130 transducer used by IL-6, defining the molecular basis of its signaling.\",\n      \"evidence\": \"Anti-gp130 vs anti-IL-6R antibody neutralization with proliferation, phosphorylation, and junB readouts in TF-1 cells\",\n      \"pmids\": [\"8360477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the IL-11-specific ligand-binding receptor chain\", \"Downstream signaling branches not resolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified IL-11Rα as the dedicated ligand-binding chain that obligately requires gp130 to assemble a functional high-affinity receptor.\",\n      \"evidence\": \"Receptor reconstitution by transfection of IL-11Rα +/- gp130 in Ba/F3 cells with radiolabeled binding and proliferation assays\",\n      \"pmids\": [\"8637716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor stoichiometry and structural architecture not defined\", \"Downstream effectors not dissected\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Resolved early intracellular branching, showing IL-11 activates JAK kinases, MAPKs, and pp90rsk, with pp90rsk—not STAT91 alone—critical for primary response gene induction.\",\n      \"evidence\": \"Kinase assays and H7 inhibitor studies with gene expression analysis in mouse preadipocytes\",\n      \"pmids\": [\"7545369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacological inhibitor specificity limits causal assignment\", \"Relative contribution of ERK vs STAT to phenotype unresolved\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Defined upstream control of IL-11, showing IL-1α and TGFβ synergistically induce its transcription in lung fibroblasts via pathways distinct from IL-6 regulation.\",\n      \"evidence\": \"ELISA, Northern blot, nuclear run-on, and pharmacological dissection in human lung fibroblasts\",\n      \"pmids\": [\"8133053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factors mediating induction not identified\", \"Cell-type specificity of regulation not addressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated that a soluble IL-11Rα can signal in trans via gp130 but also act as an antagonist by sequestering limiting gp130, establishing dual modes of receptor function.\",\n      \"evidence\": \"Recombinant soluble receptor with Kd measurements, phosphorylation, and differentiation/proliferation assays\",\n      \"pmids\": [\"9373251\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological source of soluble receptor not identified at this stage\", \"In vivo relevance of trans-signaling not tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed concentration-dependent signaling output, with low-dose IL-11 conferring STAT3/MAPK- and protein-synthesis-dependent cytoprotection without NF-κB activation.\",\n      \"evidence\": \"Phosphorylation Western blots, MEK inhibitor PD98059, and CTL/complement cytotoxicity assays in HUVECs\",\n      \"pmids\": [\"10725745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream cytoprotective effectors not yet identified\", \"Single endothelial system\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified survivin induction as a concrete cytoprotective effector of IL-11 in endothelium in vivo.\",\n      \"evidence\": \"Human skin graft/SCID alloinjury model with survivin antisense oligonucleotide and immunohistochemistry\",\n      \"pmids\": [\"14734714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling link from receptor to survivin not mapped\", \"Single antisense approach\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed IL-11Rα as a required downstream effector of IL-13-driven airway inflammation, fibrosis, and remodeling, linking IL-11 to type 2 tissue pathology.\",\n      \"evidence\": \"IL-11Rα null mice crossed to IL-13 transgenics with histology and gene expression\",\n      \"pmids\": [\"15699166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell type mediating IL-11Rα effects not defined\", \"Signaling pathway downstream not dissected\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped the transcriptional machinery inducing IL-11, implicating AP-1/c-Jun and ERK/p38 MAPK with p38-dependent mRNA stabilization in myofibroblasts.\",\n      \"evidence\": \"EMSA, dominant-negative c-Jun adenovirus, MAPK inhibitors, ELISA, and Northern blot in intestinal myofibroblasts\",\n      \"pmids\": [\"12760902\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of AP-1 control not tested\", \"Did not link induced IL-11 to a phenotype\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established endogenous IL-11/IL-11Rα as required for type 2 airway inflammation and, separately, as a STAT3-driven promoter of gastric inflammation and tumorigenesis, revealing both inflammatory and oncogenic roles.\",\n      \"evidence\": \"IL-11Rα null mice with OVA challenge and IL-11 mutein antagonist; gp130/IL-11Rα/STAT genetic models with STAT3 antisense oligonucleotides\",\n      \"pmids\": [\"18617680\", \"18431520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific source of pathogenic IL-11 not resolved\", \"Mechanistic separation of STAT1 vs STAT3 contributions incomplete\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Extended IL-11/IL-11Rα function across reproduction, neuroprotection, and additional MAPK-driven induction pathways, showing context-dependent protective and pathogenic roles.\",\n      \"evidence\": \"PEGylated IL-11 antagonist in decidualization; IL-11Rα null EAE model with neuroprotection assays; Raf/MEK/ERK/MSK1/CREB dissection of IL-17F-induced IL-11\",\n      \"pmids\": [\"19144959\", \"19734214\", \"19251839\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific receptor requirement not isolated genetically\", \"Opposing protective vs pathogenic outcomes not mechanistically reconciled\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided human genetic proof that loss of IL-11Rα-mediated signaling causes a developmental syndrome of craniosynostosis and dental anomalies.\",\n      \"evidence\": \"Homozygosity mapping, mutational analysis, transfection signaling assays, and Il11ra null mouse phenotyping\",\n      \"pmids\": [\"21741611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting IL-11 to suture and tooth biology not defined\", \"Did not address fibrosis roles\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked IL-11 to hypoxic tumor biology, showing HIF-1/AP-1-driven, VHL-regulated IL-11 supports autocrine STAT1-dependent anchorage-independent growth.\",\n      \"evidence\": \"Promoter reporter/mutagenesis, IL-11/STAT1 siRNA, VHL reconstitution, and xenograft models\",\n      \"pmids\": [\"23549086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"STAT1 vs STAT3 selectivity in this context not fully explained\", \"Single tumor model\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed receptor-intrinsic transcytosis and identified additional transcriptional inducers, broadening IL-11 receptor functions beyond classical signaling.\",\n      \"evidence\": \"Polarized transcytosis assays with IL-11R1 intracellular domain swaps; HMGA2 ChIP-PCR and reporter assays in colorectal cancer\",\n      \"pmids\": [\"27425614\", \"26964871\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological cargo/role of transcytosis in vivo unclear\", \"Trafficking machinery for transcytosis not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Reframed IL-11 as the dominant TGFβ1-induced, fibroblast-autocrine driver of fibrosis acting through non-canonical ERK signaling, and placed IL-11 downstream of stromal LKB1 loss in tumorigenesis.\",\n      \"evidence\": \"Imaging-genomics of human fibroblasts, fibroblast-specific transgenic and Il11ra1 knockout mice with ERK assays; mesenchymal Lkb1 conditional knockout with ruxolitinib\",\n      \"pmids\": [\"29160304\", \"29202476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular steps from ERK to fibrogenic translation not yet detailed\", \"Contribution of STAT3 not fully excluded across tissues\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated IL-11-driven autocrine JAK signaling underlies therapy resistance in cancer, expanding its oncogenic signaling repertoire.\",\n      \"evidence\": \"qHTCS screen, anti-IL-11 antibody, and JAK2 inhibitor in ovarian cancer in vitro and xenografts\",\n      \"pmids\": [\"29662190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JAK2-STAT5 axis not validated genetically\", \"Single cancer context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined cell-type-specific and senescence-linked fibrotic mechanisms and structurally established gp130's selectivity for IL-11 signaling.\",\n      \"evidence\": \"Fibroblast-specific Il11ra1 conditional knockout in bleomycin lung injury; Bmi-1/p16INK4a models of the TGFβ1/IL-11/MEK/ERK axis; IL6ST p.R279Q genome-edited mice and patient cells\",\n      \"pmids\": [\"32656894\", \"31959867\", \"32566365\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How fibroblast ERK signaling relays to immune STAT3/NF-κB not fully mapped\", \"Structural basis of gp130 selectivity for IL-11 not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Consolidated the non-canonical ERK/mTOR translational mechanism of fibrogenesis, distinguished it from transient STAT3 signaling, identified RHBDL2-mediated soluble receptor generation, and expanded inflammatory/oncogenic roles including CD4+ T cell suppression and hepatotoxicity.\",\n      \"evidence\": \"Il11ra1-null fibroblasts with ERK/mTOR/P70RSK and EPRS ribosome-stalling analysis; RHBDL2 cleavage-site mutagenesis with trans-signaling assays; Il11 knockout and germline/hepatocyte-specific Il11ra1 models in lung and liver injury; CD4+ T cell adoptive transfer and depletion; MAFF-BACH1 and piR-2158 promoter studies\",\n      \"pmids\": [\"34651016\", \"33566379\", \"34239012\", \"34108253\", \"33906864\", \"33590875\", \"36012165\", \"34262028\", \"37153732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of IL-11Rα-dependent vs -independent STAT3 activation incomplete\", \"Relative in vivo weight of trans-signaling vs classical signaling unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified the core IL-11/ERK/P90RSK/LKB1/AMPK/mTOR signaling axis and extended IL-11 fibrosis biology to vascular and pancreatic stromal disease.\",\n      \"evidence\": \"Phospho-LKB1 S325/S428 mapping with AMPK/mTOR and metformin studies; Fbn1 Marfan mouse with Il11ra1 knockout and anti-IL11RA antibody; PSC IL-11 vs IL-6 comparison with anti-IL11RA antibody\",\n      \"pmids\": [\"35992082\", \"35135328\", \"35408908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct kinase responsible for LKB1 phosphorylation context not fully defined\", \"Why ERK is sustained selectively by IL-11 vs IL-6 unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended IL-11 to innate immune amplification via NLRP3 inflammasome activation in monocytes and detailed STAT3/ERK-dependent renal EMT, with druggable competitive inhibition.\",\n      \"evidence\": \"scRNA-seq of IL-11-stimulated PBMCs and MS CSF cells with anti-IL-11 mAb in EAE; RTEC STAT3/ERK-metadherin dissection with micheliolide competitive binding and UUO model\",\n      \"pmids\": [\"37339207\", \"37673330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct receptor-to-NLRP3 signaling steps not fully mapped\", \"Micheliolide binding-site mechanism inferred indirectly\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established IL-11 as a driver of organismal aging via the ERK-AMPK-mTORC1 axis, and uncovered post-transcriptional (m6A) regulation and a non-canonical EGFR ligand role expanding its signaling biology.\",\n      \"evidence\": \"Il11/Il11ra1 knockout and anti-IL-11 lifespan/metabolic studies; ALKBH5 RIP-seq and macrophage-specific knockout with rescue; astrocyte IL-11/EGFR brain metastasis models; IL-11/JAK1/STAT4-CBP-c-MYC in prostate cancer\",\n      \"pmids\": [\"39020175\", \"38443404\", \"38696655\", \"38429845\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"EGFR-as-IL-11-receptor not independently replicated\", \"JAK1/STAT4 pathway novel and not yet confirmed in other contexts\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how IL-11 selectively sustains non-canonical ERK signaling versus transient STAT3, and what determines its opposing protective versus pathogenic outcomes across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model explaining receptor-level bias toward ERK vs STAT3\", \"Mechanistic basis for IL-11Rα-independent STAT3 activation by recombinant IL-11 unexplained\", \"Physiological balance of classical vs trans- vs transcytotic signaling in vivo unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 18, 32]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [3, 18, 34]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 28, 40]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 18, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 24, 31, 37]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13, 30, 35]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [23, 32]}\n    ],\n    \"complexes\": [\"IL-11Rα/gp130 receptor complex\"],\n    \"partners\": [\"IL11RA\", \"IL6ST\", \"EGFR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}