{"gene":"IL11","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1993,"finding":"IL-11 signals through the same gp130 signal transducer as IL-6, despite using a distinct ligand-binding protein. 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 blocked IL-6 but not IL-11 signaling.","method":"Neutralizing antibody blockade in TF-1 cells (anti-gp130, anti-IL-6R); protein tyrosine phosphorylation assay; junB mRNA expression","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal antibody blockade with multiple functional readouts, foundational mechanism paper","pmids":["8360477"],"is_preprint":false},{"year":1995,"finding":"IL-11 activates JAK tyrosine kinases, MAP kinases, and pp90rsk; pp90rsk is identified as an H7-sensitive protein kinase critical for primary response gene (junB, tis11, tis8, MAP kinase phosphatase) expression induced by IL-11. Tyrosine phosphorylation of Stat91 is involved but insufficient alone for primary response gene activation.","method":"Kinase activation assays, H7 inhibitor studies, primary response gene expression analysis in mouse preadipocytes","journal":"Annals of the New York Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple kinase readouts in defined cell system, single lab","pmids":["7545369"],"is_preprint":false},{"year":1992,"finding":"The human IL11 gene is located on chromosome 19q13.3-q13.4, spans 7 kb, contains five exons and four introns, and has two polyadenylation sites corresponding to 2.5- and 1.5-kb transcripts. The 5'-flanking region contains cytokine-like regulatory elements and a sequence with 71% similarity to the IL1-responsive element of IL6.","method":"Genomic cloning, in situ hybridization, sequence analysis","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — direct genomic characterization with chromosomal mapping","pmids":["1386338"],"is_preprint":false},{"year":1994,"finding":"Histamine synergizes with TGF-β1 to augment IL-11 production in human lung fibroblasts via H1 receptors and a calcium/calmodulin-dependent pretranslational mechanism; H2 receptor agonists and cAMP-dependent pathways were not involved. TGF-β1 alone did not alter cytosolic Ca2+, but histamine caused biphasic Ca2+ increase and sustained oscillations in the presence of TGF-β1.","method":"IL-11 protein and mRNA quantification, H1/H2 receptor antagonist/agonist pharmacology, calmodulin antagonists, intracellular Ca2+ chelation and imaging","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal pharmacological dissections with mechanistic readouts","pmids":["7963541"],"is_preprint":false},{"year":2017,"finding":"IL-11 is the dominant transcriptional response of human fibroblasts to TGFβ1 and is required for TGFβ1's pro-fibrotic effect. IL-11 and IL-11RA are expressed specifically in fibroblasts, where IL-11 drives non-canonical, ERK-dependent autocrine signaling that is required for fibrogenic protein synthesis. Fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis in mice, while Il11ra1 deletion protects against fibrosis.","method":"Integrated imaging-genomics of primary human fibroblasts; fibroblast-specific transgenic and knockout mice; IL-11 injection; neutralizing antibodies; ERK pathway analysis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal gain- and loss-of-function approaches in human cells and mice, replicated across organs","pmids":["29160304"],"is_preprint":false},{"year":2011,"finding":"Homozygous loss-of-function mutations in IL11RA cause a human syndrome of craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. A specific IL11RA missense mutation (p.Arg296Trp) rendered the receptor unable to mediate IL-11 signaling in cell transfection experiments, demonstrating that IL-11 signaling restricts suture fusion and tooth number.","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 — human genetics combined with functional receptor signaling assay and mouse knockout phenotype","pmids":["21741611"],"is_preprint":false},{"year":2013,"finding":"IL11 is a hypoxia-inducible, VHL-regulated gene in human cancer cells; HIF-1 and AP-1 cooperate to activate the IL11 promoter under hypoxic conditions. Hypoxic cancer cells express functional IL-11Rα, enabling autocrine IL-11 signaling that promotes anchorage-independent growth and tumor growth in vivo; silencing IL11 or STAT1 abrogated these hypoxia-induced effects.","method":"Reporter assay (IL11 promoter), VHL manipulation, siRNA knockdown, anchorage-independent growth assay, xenograft tumor models","journal":"Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — promoter dissection, loss-of-function genetics, and in vivo tumor model in single rigorous study","pmids":["23549086"],"is_preprint":false},{"year":2012,"finding":"IL-11 mediates cardioprotection against ischemia/reperfusion injury through cardiac STAT3 activation; STAT3 conditional knockout mice lost IL-11-mediated protection and failed to suppress reactive oxygen species production after I/R, establishing a cardiac IL-11→STAT3→ROS suppression axis.","method":"Mouse I/R model, intravenous IL-11 administration, cardiac-specific STAT3 conditional knockout, TTC staining, echocardiography, dihydroethidium fluorescence","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (STAT3 CKO) plus functional cardiac phenotype readouts","pmids":["22707562"],"is_preprint":false},{"year":2021,"finding":"IL-11 signals in fibroblasts via IL6ST (gp130); IL-11-induced ERK activation (not STAT3) drives fibrogenesis and myofibroblast transformation. ERK activates an mTOR/P70RSK protein translation axis; selectivity for Collagen 1 synthesis is ascribed to an EPRS-regulated ribosome stalling mechanism. STAT3 inhibition caused proteotoxic ER stress and cell death unrelated to fibrogenesis. Recombinant human IL-11 increases pSTAT3 in Il11ra1-null fibroblasts, indicating off-target STAT3 effects of species-mismatched recombinant protein.","method":"Pharmacological inhibitors (ERK, STAT3, mTOR), Il11ra1 knockout fibroblasts, ER stress markers, collagen synthesis assays, proteomics","journal":"Frontiers in molecular biosciences","confidence":"High","confidence_rationale":"Tier 1–2 — mechanistic dissection with multiple inhibitors plus genetic knockout controls, identifies specific translation mechanism","pmids":["34651016"],"is_preprint":false},{"year":2022,"finding":"IL-11 stimulates ERK/P90RSK-mediated phosphorylation of LKB1 at S325 and S428, causing LKB1 inactivation, AMPK inhibition, and mTOR activation across stromal, epithelial, and cancer cell types, driving a mesenchymal/fibrogenic program. Metformin-stimulated AMPK activation inhibited IL-11-induced phenotypes.","method":"Phospho-proteomic analysis, site-specific LKB1 mutagenesis, pharmacological AMPK activation (metformin), genetic and pharmacologic IL-11 manipulation in mice with fatty liver disease","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1–2 — direct identification of phosphorylation sites plus mutagenesis and in vivo epistasis","pmids":["35992082"],"is_preprint":false},{"year":2024,"finding":"IL-11 regulates an ERK-AMPK-mTORC1 axis that modulates aging pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline and frailty; anti-IL-11 treatment from 75 weeks extends median lifespan of mice by ~22–25%, establishing IL-11 as a driver of mammalian aging via this metabolic signaling axis.","method":"Genetic deletion (Il11-/-, Il11ra1-/-), anti-IL-11 antibody treatment, lifespan studies, metabolic and frailty phenotyping in aged mice","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacologic loss-of-function with quantitative lifespan endpoint, replicated across sexes","pmids":["39020175"],"is_preprint":false},{"year":2021,"finding":"ALKBH5-mediated m6A demethylation of IL-11 mRNA increases its stability and protein levels in macrophages, promoting macrophage-to-myofibroblast transition (MMT) and cardiac fibrosis under angiotensin II-induced hypertension. Macrophage-specific ALKBH5 knockout inhibited MMT and reduced cardiac fibrosis.","method":"RNA immunoprecipitation sequencing (RIP-seq), m6A modification assays, macrophage-specific ALKBH5 knockout, single-cell transcriptomics, lineage tracing, IL11 overexpression rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 — RIP-seq identifies IL-11 mRNA as ALKBH5 target, genetic knockout with rescue experiment","pmids":["38443404"],"is_preprint":false},{"year":2021,"finding":"IL-11 signals through gp130 to activate JAK/STAT3 in tumor epithelia upon stromal Lkb1 deletion in gastrointestinal tumorigenesis. JAK1/2 inhibition with ruxolitinib dramatically decreased polyposis in LKB1-deficient mice, placing IL-11/JAK/STAT3 as essential downstream of stromal Lkb1 loss.","method":"Mesenchymal/fibroblast-specific Lkb1 conditional knockout, lineage tracing, immunohistochemistry, JAK1/2 inhibitor (ruxolitinib) treatment in vivo","journal":"Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis plus therapeutic inhibition in vivo","pmids":["29202476"],"is_preprint":false},{"year":2021,"finding":"In acetaminophen-induced liver injury, IL-11 secreted from APAP-damaged hepatocytes triggers an autocrine loop of NADPH oxidase 4 (NOX4)-dependent hepatocyte death downstream of mitochondrial dysfunction. Hepatocyte-specific Il11ra1 deletion or germline Il11 deletion protected mice from liver injury and was associated with reduced JNK and ERK activation and restored glutathione levels.","method":"Hepatocyte-specific and germline knockout mice, anti-IL11RA neutralizing antibody, NOX4 pathway analysis, GSH measurement, JNK/ERK western blotting","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 — cell-type specific genetic knockout plus pharmacologic validation with defined molecular mechanism","pmids":["34108253"],"is_preprint":false},{"year":2021,"finding":"IL-11 stimulates ERK activation in renal tubular epithelial cells (TECs) via p90RSK-mediated GSK3β inactivation, leading to SNAI1 upregulation, mesenchymal transition, and pro-inflammatory gene expression. TEC-specific deletion of Il11ra1 protected mice from renal injury-induced inflammation, fibrosis, and failure.","method":"TEC-specific Il11ra1 conditional knockout, ERK/p90RSK/GSK3β pathway analysis, SNAI1 expression, mouse AKI and CKD models, anti-IL11 antibody","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — cell-type specific knockout with defined signaling pathway and multiple disease models","pmids":["36470928"],"is_preprint":false},{"year":2021,"finding":"IL-11 binds the membrane-bound IL-11 receptor (IL-11R), which recruits a gp130 homodimer for classic signaling. The rhomboid intramembrane protease RHBDL2 (in addition to previously known ADAM10) cleaves IL-11R between Ala-370 and Ser-371, generating soluble IL-11R (sIL-11R) that enables IL-11 trans-signaling via gp130 homodimerization. RHBDL2 can cleave IL-11R in the early secretory pathway. The human mutation IL-11R-A370V prevents RHBDL2-mediated cleavage but not classic signaling.","method":"RHBDL2 overexpression/knockdown, cleavage site mutagenesis, sIL-11R bioactivity assay (STAT3 phosphorylation), subcellular localization studies, human mutation functional characterization","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1–2 — cleavage site identified by mutagenesis, biologically validated with trans-signaling assay, human mutation phenocopied","pmids":["33566379"],"is_preprint":false},{"year":2020,"finding":"A homozygous IL6ST variant (GP130 p.R281Q) causes selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, or CNTF signaling, demonstrating that a specific GP130 residue is required for IL-11 but not other IL-6 family cytokine signal transduction. Mice carrying the corresponding Il6st p.R279Q variant have facial synostosis and dental abnormalities phenocopying IL11RA deficiency.","method":"Transfected cell lines, primary patient-derived cells, genome-edited mouse model, cytokine panel signaling assays","journal":"Bone research","confidence":"High","confidence_rationale":"Tier 2 — selective signaling defect demonstrated in multiple cell systems and validated in mouse model","pmids":["32566365"],"is_preprint":false},{"year":2021,"finding":"IL11 stimulation of primary human fibroblasts (kidney, lung, skin) causes transient STAT3 phosphorylation but sustained ERK activation, and induces a proinflammatory secretome including IL8, IL6, MCP1, CCL20, CXCL1/5/6. IL11 induces IL33 expression (38-fold) via STAT3 (not ERK), establishing IL11 as pro-inflammatory in fibroblasts via the IL33 alarmin axis.","method":"RNA sequencing time course, proteomics/secretome analysis, STAT3 and MEK/ERK pharmacological inhibition, primary fibroblast cultures from three tissue types","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 — multi-organ fibroblast validation with orthogonal transcriptomic and proteomic readouts plus pathway-selective inhibition","pmids":["36012165"],"is_preprint":false},{"year":2020,"finding":"In the bleomycin model of lung fibrosis, fibroblast-specific deletion of Il11ra1 (CKO) reduced pulmonary fibrosis, fibroblast ERK activation, chronic immune infiltrates, NF-kB phosphorylation, and pro-inflammatory gene activation, establishing that IL-11 signaling in fibroblasts drives both fibrosis and chronic inflammation in the lung.","method":"Fibroblast-specific loxP/Cre Il11ra1 knockout (CKO mice), bleomycin lung injury model, ERK/STAT3/NF-kB signaling analysis, neutralizing antibody comparison","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 — cell-type specific genetic deletion with multiple molecular and histological readouts","pmids":["32656894"],"is_preprint":false},{"year":2021,"finding":"In Marfan syndrome aortas, IL-11 is upregulated in vascular smooth muscle cells (VSMCs) and drives ERK-dependent collagen and MMP secretion, aortic dilatation, fibrosis, and inflammation. Genetic deletion of Il11ra1 or therapeutic anti-IL11RA antibody (X209) reduced aortic COL1A1, IL11, MMP2/9, and phospho-ERK expression and attenuated aortic pathology.","method":"Fbn1C1041G/+ mouse model crossed to Il11EGFP reporter and Il11ra1-/- strains; echocardiography; immunostaining; biochemical analyses; 20-week antibody treatment study","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis plus therapeutic antibody with longitudinal imaging in established disease model","pmids":["35135328"],"is_preprint":false},{"year":2021,"finding":"TGF-β1 induces IL-11 secretion from human dermal fibroblasts (HDFs); IL-11 stimulates ERK activation leading to HDF-to-myofibroblast transformation and extracellular matrix secretion via an autocrine loop that is independent of SMAD2/3 phosphorylation and STAT3 activity. Anti-IL11 antibody or IL11RA siRNA reduced TGFβ-induced HDF proliferation, matrix production, and migration, phenocopied by ERK inhibition.","method":"Gain- and loss-of-function in primary HDFs from SSc patients and controls; ERK/SMAD2/3/STAT3 western blotting; neutralizing antibody; siRNA knockdown; myofibroblast differentiation assay","journal":"Rheumatology","confidence":"High","confidence_rationale":"Tier 2 — multiple complementary loss-of-function approaches with pathway specificity established by inhibitor panel","pmids":["33590875"],"is_preprint":false},{"year":2022,"finding":"In pancreatic stellate cells (PSCs), IL-11 stimulation causes transient STAT3 phosphorylation and sustained ERK activation, leading to PSC-to-myofibroblast transformation. IL-6 stimulation caused sustained STAT3 but no ERK activation and no PSC transformation, demonstrating pathway specificity. TGFβ, CTGF, and PDGF induced IL-11 secretion from PSCs, and autocrine IL-11/ERK activity was required for their fibrogenic effects on PSCs.","method":"PSC culture, pharmacological inhibitors, cytokine panel comparison, anti-IL11RA neutralizing antibody, pancreatic duct ligation mouse model","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 — direct pathway comparison (IL-11 vs IL-6) plus autocrine mechanism demonstrated with blocking antibody and in vivo model","pmids":["35408908"],"is_preprint":false},{"year":2021,"finding":"IL-11 expressed specifically in fibroblasts places IL-11 activity upstream of IL-6 in fibrotic lung disease: Il11-/- mice have reduced Il1b, Timp1, Ccl2, and diminished IL6 expression both at baseline and after bleomycin injury. Il11-/- female mice are infertile. Unlike Il11ra1-/- mice, Il11-/- mice do not have craniosynostosis or altered long bone mass, indicating bone development anomalies are specifically associated with IL11RA but not IL11 itself.","method":"Il11 knockout mouse generation; comparison with Il11ra1-/- mice; bleomycin lung injury model; ERK/STAT3/NF-kB signaling; cytokine profiling; fertility assessment; bone phenotyping","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — direct genetic comparison of ligand vs receptor knockout with multiple phenotypic readouts establishing pathway hierarchy","pmids":["34239012"],"is_preprint":false},{"year":2017,"finding":"HMGA2 transcription factor directly binds the IL11 promoter and activates its transcription, as demonstrated by chromatin immunoprecipitation-PCR and luciferase reporter assays. IL-11, as a direct downstream target of HMGA2, modulates cell migration and invasion through pSTAT3-dependent signaling.","method":"ChIP-PCR, luciferase reporter assay, HMGA2 overexpression/knockdown in colorectal cancer cells, STAT3 phosphorylation analysis","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding shown by ChIP plus functional rescue, single lab","pmids":["26964871"],"is_preprint":false},{"year":2021,"finding":"The HIF target MAFF forms a heterodimer with BACH1 that directly transcriptionally activates IL11, leading to STAT3 signaling and breast cancer invasion/metastasis. Combined ChIP-seq and RNA-seq identified IL11 as a direct MAFF/BACH1 transcriptional target; IL11 inhibition reduced metastasis equivalently to MAFF inhibition.","method":"ChIP-seq, RNA-seq, siRNA knockdown, MAFF/BACH1 heterodimer characterization, metastasis assays in vivo","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — ChIP-seq demonstrates direct binding plus functional equivalence of IL11 and MAFF inhibition","pmids":["34262028"],"is_preprint":false},{"year":2018,"finding":"Cancer-associated fibroblasts promote chemoresistance in gastric cancer by secreting IL-11, which activates the IL-11/IL-11R/gp130/JAK/STAT3/Bcl2 anti-apoptosis pathway in cancer cells. JAK inhibitor combined with chemotherapy overcame resistance in vivo.","method":"CAF-cancer cell co-culture, flow cytometry, western blotting, MTT assay, xenograft mouse models, JAK inhibitor treatment","journal":"Cancer research and treatment","confidence":"Medium","confidence_rationale":"Tier 2 — paracrine mechanism demonstrated with pathway inhibition and in vivo validation, single lab","pmids":["29690750"],"is_preprint":false},{"year":2023,"finding":"IL-11 induces EMT in renal tubular epithelial cells via sequential activation of STAT3 then ERK1/2 signaling and upregulation of metadherin. Micheliolide (MCL) competitively inhibits IL-11 binding to IL-11Rα1, blocking STAT3 and ERK1/2-metadherin pathways and suppressing tubular EMT.","method":"UUO mouse model, siRNA knockdown of IL-11, competitive binding assay (MCL vs IL-11), STAT3/ERK1/2/metadherin pathway analysis, DMAMC pro-drug in vivo","journal":"American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 — competitive binding assay identifies receptor interaction site, pathway sequencing by inhibitor studies, in vivo validation","pmids":["37673330"],"is_preprint":false},{"year":2018,"finding":"In platinum-resistant ovarian cancer, elevated ROS sustain high IL-11 expression via FRA1-mediated transcriptional activation. Autocrine IL-11 then constitutively activates JAK2-STAT5 signaling to confer platinum resistance. JAK2 inhibition or anti-IL-11 antibody reversed resistance in vitro and in vivo.","method":"High-throughput combinational screen, genomic sequencing, FRA1 ChIP/reporter assay, JAK2 inhibitor (LY2784544), anti-IL-11 antibody, xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway (ROS→FRA1→IL-11→JAK2-STAT5) established with ChIP, inhibitors, and in vivo validation","pmids":["29662190"],"is_preprint":false},{"year":2004,"finding":"Breast cancer cells stimulate osteoblastic production of IL-11 (via PTHrP), which in turn enhances osteoblast PGE2 release; PGE2 then downregulates GM-CSF production by spleen cells to promote osteoclast formation. Neutralizing antibody to murine IL-11 or its receptor completely prevented osteoclastogenic activity of breast cancer-conditioned medium.","method":"Osteoblast-spleen cell co-culture system, ultrafiltration fractionation, neutralizing antibodies (PTHrP, murine IL-11, murine IL-11R, GM-CSF), COX inhibitor, recombinant GM-CSF","journal":"International journal of cancer","confidence":"High","confidence_rationale":"Tier 2 — mechanistic pathway defined with specific neutralizing antibodies at each step","pmids":["14999770"],"is_preprint":false},{"year":2009,"finding":"IL-11 regulates experimental autoimmune encephalomyelitis through two mechanisms: immunoregulation (reducing T cell effector cytokine production by modulating CD11c+ APC-mediated lymphocyte activation and reducing APC population size) and direct neuroprotection (reducing apoptosis and potentiating mitosis of oligodendrocyte progenitors). IL-11Rα-null mice displayed worsened disease.","method":"IL-11Rα knockout mice, EAE model, T cell/APC co-culture, oligodendrocyte progenitor cultures, IL-11 treatment in vivo","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic knockout combined with cell-type-specific in vitro mechanistic studies","pmids":["19734214"],"is_preprint":false},{"year":2015,"finding":"IL-11 induces differentiation of CD11b+CD14+ monocytic myeloid-derived suppressor cells (MDSCs) from PBMCs via STAT3 phosphorylation activation downstream of IL-11/IL-11Rα/gp130 signaling. IL-11-conditioned MDSCs suppress T-cell proliferation via arginase-1 upregulation.","method":"PBMC culture with IL-11, flow cytometry, STAT3 phosphorylation assay, arginase-1 measurement, T-cell proliferation assay, immunohistochemistry of colorectal cancer tissue","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — STAT3 activation shown and functional MDSC suppression demonstrated, single lab","pmids":["28781374"],"is_preprint":false},{"year":2023,"finding":"IL-11 induces NLRP3 inflammasome activation in monocytes; IL-11 stimulation of monocytes upregulates NFKB1, NLRP3, IL1B, and IL18 (scRNA-seq). IL-11R+ CSF monocytes from MS patients upregulate NLRP3 inflammasome-related genes and migratory genes (VEGFA/B). Anti-IL-11 mAb treatment 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+ cell sorting from CSF, αIL-11 mAb treatment in EAE mice, flow cytometry, immunohistochemistry","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 2 — scRNA-seq mechanistic data combined with in vivo therapeutic validation","pmids":["37339207"],"is_preprint":false},{"year":2017,"finding":"The SNP rs4252548 (R112H) in IL-11 does not impair receptor binding or STAT3 signaling but reduces thermal stability of the IL-11 protein. IL-11 R112H fails to support survival of osteoclast progenitor cells, attributable to the loss of positive charge at position 112.","method":"Crystal structure molecular replacement, recombinant protein expression, receptor binding affinity assay, STAT3 phosphorylation assay, thermal stability assay, osteoclast progenitor survival assay","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"High","confidence_rationale":"Tier 1 — structural analysis plus functional receptor binding and cell-based signaling validation","pmids":["29237553"],"is_preprint":false},{"year":2022,"finding":"Sirt1 negatively regulates IL-11 transcription by deacetylating H3K9/14ac at the IL-11 promoter region (-871 to -724), which is also the major Smad2 binding region; this suppresses TGFβ1-induced IL-11/MEK/ERK signaling and senescence-associated pulmonary fibrosis.","method":"ChIP-seq/ChIP-PCR (H3K9/14ac, Smad2 binding), Sirt1 transgenic and Cyp27b1-/- mouse models, IL-11 promoter occupancy analysis, pulmonary function testing","journal":"Aging cell","confidence":"High","confidence_rationale":"Tier 1–2 — direct histone modification mapping by ChIP-seq plus Smad2 co-occupancy at defined promoter region","pmids":["35906886"],"is_preprint":false},{"year":2021,"finding":"WNT3a/β-catenin signaling in cardiac fibroblasts enhances TGFβ-induced IL-11 production and secretion via TAK1 phosphorylation (but not Smad pathway), potentiating myofibroblast transformation and collagen/fibronectin production. Anti-IL-11 antibody blocked the profibrotic effects of TGFβ+WNT3a co-stimulation.","method":"Human cardiac fibroblast culture, WNT3a/WNT5a/CHIR99021 stimulation, TAK1 phosphorylation western blotting, IL-11 ELISA, anti-IL-11 neutralizing antibody, β-catenin reporter assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — pathway-specific analysis with TAK1 phosphorylation and neutralizing antibody in primary human cells, single lab","pmids":["34576234"],"is_preprint":false},{"year":2010,"finding":"In skeletal myoblast preconditioning, IL-11 activates ERK1/2 and STAT3, and this is associated with upregulation of miR-21. miR-21 functions as a key regulator downstream of IL-11 in the ERK1/2-STAT3 signaling cascade; knockdown of miR-21, IL-11 siRNA, or ERK1/2 blockade each compromised the cytoprotective effect of preconditioning.","method":"Pharmacological preconditioning, IL-11 siRNA, ERK1/2 blocker, anti-miR-21, western blotting, in vivo cell survival assay in rat MI model","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pathway interventions in vitro with in vivo validation, single lab","pmids":["20498256"],"is_preprint":false},{"year":2024,"finding":"IL-11 acts as a ligand of EGFR in addition to its canonical IL-11Rα/gp130 receptor, activating EGFR and downstream signaling to increase PDL1 expression in brain metastasis of EGFR-mutated NSCLC, promoting immune escape. Dual targeted inhibition of gp130 and EGFR suppressed brain metastasis growth in mice.","method":"Reactive astrocyte co-culture, IL-11 EGFR binding assay, PDL1 expression analysis, T-cell apoptosis assay, gp130 and EGFR inhibitor in vivo brain metastasis model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — novel receptor interaction with functional validation and in vivo data, single study","pmids":["38696655"],"is_preprint":false},{"year":2024,"finding":"Autocrine IL-11 activates JAK1/STAT4 in docetaxel-resistant prostate cancer cells; pSTAT4 translocates to the nucleus, associates with CBP at the c-MYC promoter (ChIP-seq), and amplifies c-MYC transcriptional activity to drive resistance. Disruption of IL-11/IL-11RA autocrine loop or JAK1/STAT4 pathway restored docetaxel sensitivity.","method":"Single-cell secretion profiling, ChIP-seq (pSTAT4 genome-wide binding), co-immunoprecipitation (pSTAT4-CBP), luciferase reporter (c-MYC promoter), JAK1/STAT4 inhibitors, organoid and in vivo models","journal":"Journal of experimental & clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — ChIP-seq identifies direct binding at c-MYC promoter, co-IP shows pSTAT4-CBP interaction, functional rescue with multiple interventions","pmids":["38429845"],"is_preprint":false},{"year":2004,"finding":"IL-11 confers cytoprotection to human microvascular endothelial cells in a transplant alloinjury model by upregulating survivin expression; topical survivin antisense oligonucleotide largely abrogated the protective effect of IL-11 without affecting T cell activation or ICAM-1 expression.","method":"SCID/beige mouse human skin graft alloinjury model, intradermal IL-11 injection, survivin antisense oligonucleotide, immunohistochemistry","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — functional rescue/knockdown experiment linking IL-11 to specific effector molecule in defined in vivo model","pmids":["14734714"],"is_preprint":false},{"year":2013,"finding":"In skeletal myoblast preconditioning studies, IL-11 is upstream of ERK1/2 activation; A1 adenosine receptor activation in renal proximal tubule cells induces IL-11 expression in an ERK-dependent manner, and IL-11 is required as a critical intermediary for A1AR-mediated induction of sphingosine kinase-1 and renal protection. IL-11 receptor-deficient mice lost A1AR-mediated renal protection.","method":"CCPA (A1AR agonist) treatment of HK-2 cells and mice, IL-11 neutralizing antibody, IL-11 receptor-deficient mice, renal proximal tubule-specific A1AR knockout, ERK inhibition, sphingosine kinase-1 assay","journal":"Journal of the American Society of Nephrology","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (IL-11R-/-, A1AR KO) plus pharmacological dissection of the A1AR→ERK→IL-11→SphK1 axis","pmids":["23813214"],"is_preprint":false}],"current_model":"IL-11 is a pleiotropic cytokine of the IL-6 family that signals through a membrane receptor complex of IL-11Rα and gp130, activating ERK (the dominant pro-fibrotic pathway), STAT3 (context-dependent), and JAK kinases; downstream of ERK it phosphorylates p90RSK, inactivates LKB1/AMPK, and activates mTOR to drive collagen synthesis via an EPRS-regulated ribosome-stalling mechanism, while autocrine IL-11/ERK signaling in fibroblasts is required for TGFβ1-induced fibrogenesis across multiple organs, and IL-11 can also engage EGFR as an alternative receptor and undergo ectodomain shedding by ADAM10 or RHBDL2 to generate soluble IL-11R that enables trans-signaling through gp130 homodimerization."},"narrative":{"teleology":[{"year":1992,"claim":"Determination of IL11 gene structure and chromosomal location established the genomic framework for subsequent promoter and regulatory studies.","evidence":"Genomic cloning, in situ hybridization, and sequence analysis mapped IL11 to 19q13.3–q13.4 with five exons and IL-1-responsive regulatory elements","pmids":["1386338"],"confidence":"High","gaps":["Promoter elements not functionally validated at this stage","No information on tissue-specific transcription factors controlling IL11"]},{"year":1993,"claim":"Establishing that IL-11 signals through gp130 resolved how a distinct cytokine converges on the same signal transducer as IL-6, defining the shared receptor architecture of the IL-6 family.","evidence":"Anti-gp130 antibodies abolished IL-11-induced proliferation, tyrosine phosphorylation, and junB expression in TF-1 cells, while anti-IL-6R had no effect on IL-11 signaling","pmids":["8360477"],"confidence":"High","gaps":["Stoichiometry and structure of the IL-11Rα/gp130 signaling complex not determined","Downstream kinase cascades not yet mapped"]},{"year":1995,"claim":"Identification of JAK, MAPK, and p90RSK as IL-11-activated kinases, with p90RSK as the critical mediator of primary response gene induction, revealed that IL-11 signals through non-STAT pathways with functional importance.","evidence":"Kinase activation assays and H7 inhibitor studies in mouse preadipocytes showed p90RSK is required for junB, tis11, and tis8 expression; STAT91 tyrosine phosphorylation was insufficient alone","pmids":["7545369"],"confidence":"Medium","gaps":["Downstream substrates of p90RSK in IL-11 context not identified","Single cell system (preadipocytes)"]},{"year":2004,"claim":"Discovery of IL-11's role in osteoclastogenesis and endothelial cytoprotection extended its known biology beyond hematopoiesis to bone remodeling and vascular protection.","evidence":"Neutralizing anti-IL-11/IL-11R antibodies blocked breast cancer-induced osteoclast formation via a PTHrP→IL-11→PGE2→GM-CSF axis; separately, IL-11 upregulated survivin to protect endothelial cells in transplant alloinjury","pmids":["14999770","14734714"],"confidence":"High","gaps":["Survivin mechanism not fully resolved—single antisense approach","Direct IL-11 action on osteoclast precursors versus indirect (osteoblast-mediated) effects not separated"]},{"year":2009,"claim":"Demonstration that IL-11 exerts dual immunoregulatory and neuroprotective functions in EAE established it as an anti-inflammatory cytokine in CNS autoimmunity.","evidence":"IL-11Rα-null mice had worsened EAE; IL-11 reduced T cell effector cytokines via APC modulation and directly promoted oligodendrocyte progenitor survival","pmids":["19734214"],"confidence":"High","gaps":["Cell-type-specific contribution (APC vs oligodendrocyte) not genetically separated","Whether IL-11 is protective or pathogenic in other neuroinflammatory contexts unknown"]},{"year":2011,"claim":"Human genetic evidence that IL11RA loss-of-function causes craniosynostosis and dental anomalies established IL-11 signaling as essential for craniofacial and dental development.","evidence":"Homozygosity mapping identified IL11RA mutations; the p.Arg296Trp mutation abolished IL-11 signaling in transfection assays; Il11ra-null mice phenocopied the human syndrome","pmids":["21741611"],"confidence":"High","gaps":["Downstream effectors of IL-11 in suture biology not identified","Whether IL-11 itself (vs other IL-11Rα ligands) is the relevant signal in vivo not distinguished until later"]},{"year":2012,"claim":"Demonstration that cardiac IL-11 protection against ischemia/reperfusion requires STAT3 established a tissue-protective signaling axis distinct from later fibrotic mechanisms.","evidence":"Cardiac-specific STAT3 conditional knockout mice lost IL-11-mediated cardioprotection and failed to suppress ROS after I/R","pmids":["22707562"],"confidence":"High","gaps":["Whether ERK also contributes to cardioprotection not tested","Acute protective role later reinterpreted in light of chronic fibrotic signaling—reconciliation incomplete"]},{"year":2013,"claim":"Discovery that IL11 is a hypoxia/HIF-1-inducible gene with autocrine tumor-promoting activity linked IL-11 to the cancer microenvironment; separately, IL-11 was identified as a required intermediary in A1AR-mediated renal protection.","evidence":"VHL manipulation and promoter dissection showed HIF-1/AP-1 cooperation at IL11 promoter; IL-11 knockdown abolished hypoxia-driven anchorage-independent growth and xenograft growth. In kidney, IL-11R-deficient mice lost A1AR-mediated protection via an ERK→IL-11→SphK1 axis","pmids":["23549086","23813214"],"confidence":"High","gaps":["Relative contributions of classic vs trans-signaling in tumor microenvironment unknown","Whether renal protective and fibrotic IL-11 effects use the same downstream signaling not resolved"]},{"year":2017,"claim":"The paradigm-shifting discovery that IL-11 is the dominant TGF-β1 target in fibroblasts and drives organ fibrosis via autocrine ERK signaling reframed IL-11 from a hematopoietic cytokine to a master fibrogenic factor.","evidence":"Integrated imaging-genomics in primary human fibroblasts; fibroblast-specific Il11 transgenics caused heart/kidney fibrosis; Il11ra1 deletion protected against fibrosis; ERK pathway was required","pmids":["29160304"],"confidence":"High","gaps":["Mechanism by which ERK selectively drives collagen translation not yet elucidated","Whether STAT3 activation is an artifact of species-mismatched recombinant IL-11 not yet formally tested"]},{"year":2020,"claim":"A specific gp130 residue (R281) was shown to be selectively required for IL-11 signaling, and fibroblast-specific IL-11Rα deletion proved sufficient to prevent lung fibrosis and chronic inflammation, demonstrating cell-autonomous fibroblast IL-11 signaling as the driver.","evidence":"GP130 p.R281Q human variant and mouse Il6st p.R279Q knock-in abolished IL-11 but not IL-6/OSM/LIF signaling, phenocopying IL11RA deficiency; fibroblast-specific Il11ra1 CKO reduced bleomycin-induced fibrosis, ERK activation, and NF-κB phosphorylation","pmids":["32566365","32656894"],"confidence":"High","gaps":["Structural basis for gp130 R281 selectivity not determined","Whether gp130 homodimer engagement differs between classic and trans-signaling not resolved"]},{"year":2021,"claim":"Mechanistic dissection revealed that IL-11-induced ERK activates mTOR/P70RSK and collagen synthesis via EPRS-regulated ribosome stalling, while STAT3 activation causes ER stress; concurrently, RHBDL2 was identified as a second IL-11Rα sheddase enabling trans-signaling, and IL-11 was shown to drive fibrosis, injury, and inflammation across kidney, liver, skin, lung, and vasculature through organ-specific ERK-dependent programs.","evidence":"ERK/STAT3/mTOR inhibitor panels in Il11ra1-KO fibroblasts established ERK–mTOR–EPRS axis for collagen synthesis; RHBDL2 cleavage site (A370–S371) identified by mutagenesis; hepatocyte-specific and TEC-specific Il11ra1 deletions protected against APAP liver injury (NOX4/JNK-dependent) and kidney injury (p90RSK/GSK3β/SNAI1-dependent); Il11-KO mice showed reduced IL-6 and pro-inflammatory cytokines and female infertility","pmids":["34651016","33566379","34108253","36470928","34239012","35135328","33590875"],"confidence":"High","gaps":["How EPRS ribosome stalling selectively controls collagen mRNAs not structurally resolved","Relative contribution of classic versus trans-signaling in each organ not quantified","Discrepancy between Il11-KO (no craniosynostosis) and Il11ra1-KO (craniosynostosis) suggests IL-11Rα has IL-11-independent roles not yet defined"]},{"year":2022,"claim":"Identification of ERK/P90RSK-mediated LKB1 phosphorylation (S325, S428) as the mechanism linking IL-11 to AMPK inhibition and mTOR activation unified the metabolic and fibrogenic arms of IL-11 signaling.","evidence":"Phosphoproteomics identified LKB1 phosphorylation sites; site-specific LKB1 mutagenesis blocked IL-11 effects; metformin-stimulated AMPK activation inhibited IL-11 phenotypes in fatty liver disease models","pmids":["35992082"],"confidence":"High","gaps":["Whether LKB1 inactivation is the sole link to mTOR or parallel pathways exist","Tissue-specificity of LKB1 phosphorylation by IL-11 not systematically assessed"]},{"year":2022,"claim":"Epigenetic regulation of IL11 transcription was defined: Sirt1 deacetylates H3K9/14ac at the IL11 promoter (overlapping the Smad2 binding region) to suppress TGF-β1-induced IL-11 expression, connecting aging-associated epigenetic changes to fibrosis.","evidence":"ChIP-seq/ChIP-PCR mapped H3K9/14ac and Smad2 co-occupancy at IL11 promoter (-871 to -724); Sirt1 transgenic mice resisted pulmonary fibrosis","pmids":["35906886"],"confidence":"High","gaps":["Whether other sirtuins or HDACs regulate IL11 not tested","Chromatin context in non-fibroblast cell types unknown"]},{"year":2024,"claim":"Genetic deletion or antibody neutralization of IL-11 in aged mice extended lifespan by ~22–25%, establishing the ERK–AMPK–mTORC1 axis driven by IL-11 as a determinant of mammalian aging.","evidence":"Il11-/- and Il11ra1-/- mice showed improved metabolic parameters; anti-IL-11 antibody treatment from 75 weeks extended median lifespan in both sexes","pmids":["39020175"],"confidence":"High","gaps":["Tissue sources of IL-11 driving systemic aging not resolved","Whether lifespan extension reflects fibrosis reduction, metabolic improvement, or both","Human translational relevance not yet tested"]},{"year":2024,"claim":"IL-11 was identified as an EGFR ligand, expanding the receptor repertoire beyond IL-11Rα/gp130, and an autocrine IL-11/JAK1/STAT4/c-MYC axis was found to drive chemoresistance in prostate cancer.","evidence":"IL-11 binding to EGFR demonstrated in brain metastasis model, with dual gp130/EGFR inhibition suppressing growth; ChIP-seq showed pSTAT4 binding at c-MYC promoter with CBP co-IP in docetaxel-resistant prostate cancer","pmids":["38696655","38429845"],"confidence":"Medium","gaps":["EGFR interaction is from a single study and awaits independent confirmation","STAT4 pathway in IL-11 signaling is novel and not yet replicated across systems","Structural basis of IL-11/EGFR interaction unknown"]},{"year":null,"claim":"Key unresolved questions include: the structural basis of the IL-11/IL-11Rα/gp130 hexameric complex at atomic resolution, the mechanism by which EPRS-dependent ribosome stalling selectively controls collagen translation, the relative contribution of classic versus trans-signaling in each disease context, reconciliation of IL-11's acute protective versus chronic pathogenic roles in the same organs, and the identity of the dominant cellular sources of IL-11 driving systemic aging.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the complete IL-11 signaling complex","EPRS ribosome stalling selectivity mechanism unresolved","Classic vs trans-signaling contributions not quantified in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,4,7,8,13,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,9,10,29]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[4,15,17,20]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,4,8,9,14,16]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[29,30,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,12,25,27,37]},{"term_id":"R-HSA-1474244","term_label":"Extracellular matrix organization","supporting_discovery_ids":[4,18,19,20,21]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[11]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[13,38]}],"complexes":["IL-11/IL-11Rα/gp130 signaling complex"],"partners":["IL6ST","IL11RA","STAT3","MAPK1","RPS6KA1","STK11","EGFR"],"other_free_text":[]},"mechanistic_narrative":"IL-11 is a pleiotropic IL-6 family cytokine that signals through an IL-11Rα/gp130 receptor complex to activate ERK, JAK/STAT, and downstream metabolic effectors, functioning as a central mediator of organ fibrosis, tissue injury responses, immune modulation, and aging-associated metabolic decline. In fibroblasts and epithelial cells, TGF-β1 induces IL-11 secretion, which engages an autocrine ERK-dependent loop—via p90RSK-mediated LKB1 inactivation, AMPK suppression, and mTOR activation—to drive collagen synthesis through an EPRS-regulated ribosome-stalling mechanism and myofibroblast transformation across heart, lung, kidney, liver, skin, and pancreas [PMID:29160304, PMID:34651016, PMID:35992082]. IL-11 trans-signaling is enabled by ectodomain shedding of IL-11Rα by RHBDL2 or ADAM10, generating soluble IL-11R that activates gp130 homodimers on cells lacking membrane IL-11Rα [PMID:33566379]; a specific gp130 residue (R281) is selectively required for IL-11 but not other IL-6-family cytokine signaling [PMID:32566365]. Homozygous loss-of-function mutations in IL11RA cause craniosynostosis and dental anomalies in humans [PMID:21741611], while genetic deletion or antibody neutralization of IL-11 in aged mice extends lifespan by ~22–25% through relief of the ERK–AMPK–mTORC1 metabolic axis [PMID:39020175]."},"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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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 blocked IL-6 but not IL-11 signaling.\",\n      \"method\": \"Neutralizing antibody blockade in TF-1 cells (anti-gp130, anti-IL-6R); protein tyrosine phosphorylation assay; junB mRNA expression\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal antibody blockade with multiple functional readouts, foundational mechanism 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 is identified as an H7-sensitive protein kinase critical for primary response gene (junB, tis11, tis8, MAP kinase phosphatase) expression induced by IL-11. Tyrosine phosphorylation of Stat91 is involved but insufficient alone for primary response gene activation.\",\n      \"method\": \"Kinase activation assays, H7 inhibitor studies, primary response gene expression analysis in mouse preadipocytes\",\n      \"journal\": \"Annals of the New York Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple kinase readouts in defined cell system, single lab\",\n      \"pmids\": [\"7545369\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The human IL11 gene is located on chromosome 19q13.3-q13.4, spans 7 kb, contains five exons and four introns, and has two polyadenylation sites corresponding to 2.5- and 1.5-kb transcripts. The 5'-flanking region contains cytokine-like regulatory elements and a sequence with 71% similarity to the IL1-responsive element of IL6.\",\n      \"method\": \"Genomic cloning, in situ hybridization, sequence analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct genomic characterization with chromosomal mapping\",\n      \"pmids\": [\"1386338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Histamine synergizes with TGF-β1 to augment IL-11 production in human lung fibroblasts via H1 receptors and a calcium/calmodulin-dependent pretranslational mechanism; H2 receptor agonists and cAMP-dependent pathways were not involved. TGF-β1 alone did not alter cytosolic Ca2+, but histamine caused biphasic Ca2+ increase and sustained oscillations in the presence of TGF-β1.\",\n      \"method\": \"IL-11 protein and mRNA quantification, H1/H2 receptor antagonist/agonist pharmacology, calmodulin antagonists, intracellular Ca2+ chelation and imaging\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal pharmacological dissections with mechanistic readouts\",\n      \"pmids\": [\"7963541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-11 is the dominant transcriptional response of human fibroblasts to TGFβ1 and is required for TGFβ1's pro-fibrotic effect. IL-11 and IL-11RA are expressed specifically in fibroblasts, where IL-11 drives non-canonical, ERK-dependent autocrine signaling that is required for fibrogenic protein synthesis. Fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis in mice, while Il11ra1 deletion protects against fibrosis.\",\n      \"method\": \"Integrated imaging-genomics of primary human fibroblasts; fibroblast-specific transgenic and knockout mice; IL-11 injection; neutralizing antibodies; ERK pathway analysis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal gain- and loss-of-function approaches in human cells and mice, replicated across organs\",\n      \"pmids\": [\"29160304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Homozygous loss-of-function mutations in IL11RA cause a human syndrome of craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. A specific IL11RA missense mutation (p.Arg296Trp) rendered the receptor unable to mediate IL-11 signaling in cell transfection experiments, demonstrating that IL-11 signaling restricts suture fusion and tooth number.\",\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 — human genetics combined with functional receptor signaling assay and mouse knockout phenotype\",\n      \"pmids\": [\"21741611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IL11 is a hypoxia-inducible, VHL-regulated gene in human cancer cells; HIF-1 and AP-1 cooperate to activate the IL11 promoter under hypoxic conditions. Hypoxic cancer cells express functional IL-11Rα, enabling autocrine IL-11 signaling that promotes anchorage-independent growth and tumor growth in vivo; silencing IL11 or STAT1 abrogated these hypoxia-induced effects.\",\n      \"method\": \"Reporter assay (IL11 promoter), VHL manipulation, siRNA knockdown, anchorage-independent growth assay, xenograft tumor models\",\n      \"journal\": \"Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — promoter dissection, loss-of-function genetics, and in vivo tumor model in single rigorous study\",\n      \"pmids\": [\"23549086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IL-11 mediates cardioprotection against ischemia/reperfusion injury through cardiac STAT3 activation; STAT3 conditional knockout mice lost IL-11-mediated protection and failed to suppress reactive oxygen species production after I/R, establishing a cardiac IL-11→STAT3→ROS suppression axis.\",\n      \"method\": \"Mouse I/R model, intravenous IL-11 administration, cardiac-specific STAT3 conditional knockout, TTC staining, echocardiography, dihydroethidium fluorescence\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (STAT3 CKO) plus functional cardiac phenotype readouts\",\n      \"pmids\": [\"22707562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 signals in fibroblasts via IL6ST (gp130); IL-11-induced ERK activation (not STAT3) drives fibrogenesis and myofibroblast transformation. ERK activates an mTOR/P70RSK protein translation axis; selectivity for Collagen 1 synthesis is ascribed to an EPRS-regulated ribosome stalling mechanism. STAT3 inhibition caused proteotoxic ER stress and cell death unrelated to fibrogenesis. Recombinant human IL-11 increases pSTAT3 in Il11ra1-null fibroblasts, indicating off-target STAT3 effects of species-mismatched recombinant protein.\",\n      \"method\": \"Pharmacological inhibitors (ERK, STAT3, mTOR), Il11ra1 knockout fibroblasts, ER stress markers, collagen synthesis assays, proteomics\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mechanistic dissection with multiple inhibitors plus genetic knockout controls, identifies specific translation mechanism\",\n      \"pmids\": [\"34651016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-11 stimulates ERK/P90RSK-mediated phosphorylation of LKB1 at S325 and S428, causing LKB1 inactivation, AMPK inhibition, and mTOR activation across stromal, epithelial, and cancer cell types, driving a mesenchymal/fibrogenic program. Metformin-stimulated AMPK activation inhibited IL-11-induced phenotypes.\",\n      \"method\": \"Phospho-proteomic analysis, site-specific LKB1 mutagenesis, pharmacological AMPK activation (metformin), genetic and pharmacologic IL-11 manipulation in mice with fatty liver disease\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct identification of phosphorylation sites plus mutagenesis and in vivo epistasis\",\n      \"pmids\": [\"35992082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-11 regulates an ERK-AMPK-mTORC1 axis that modulates aging pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline and frailty; anti-IL-11 treatment from 75 weeks extends median lifespan of mice by ~22–25%, establishing IL-11 as a driver of mammalian aging via this metabolic signaling axis.\",\n      \"method\": \"Genetic deletion (Il11-/-, Il11ra1-/-), anti-IL-11 antibody treatment, lifespan studies, metabolic and frailty phenotyping in aged mice\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacologic loss-of-function with quantitative lifespan endpoint, replicated across sexes\",\n      \"pmids\": [\"39020175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ALKBH5-mediated m6A demethylation of IL-11 mRNA increases its stability and protein levels in macrophages, promoting macrophage-to-myofibroblast transition (MMT) and cardiac fibrosis under angiotensin II-induced hypertension. Macrophage-specific ALKBH5 knockout inhibited MMT and reduced cardiac fibrosis.\",\n      \"method\": \"RNA immunoprecipitation sequencing (RIP-seq), m6A modification assays, macrophage-specific ALKBH5 knockout, single-cell transcriptomics, lineage tracing, IL11 overexpression rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — RIP-seq identifies IL-11 mRNA as ALKBH5 target, genetic knockout with rescue experiment\",\n      \"pmids\": [\"38443404\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 signals through gp130 to activate JAK/STAT3 in tumor epithelia upon stromal Lkb1 deletion in gastrointestinal tumorigenesis. JAK1/2 inhibition with ruxolitinib dramatically decreased polyposis in LKB1-deficient mice, placing IL-11/JAK/STAT3 as essential downstream of stromal Lkb1 loss.\",\n      \"method\": \"Mesenchymal/fibroblast-specific Lkb1 conditional knockout, lineage tracing, immunohistochemistry, JAK1/2 inhibitor (ruxolitinib) treatment in vivo\",\n      \"journal\": \"Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis plus therapeutic inhibition in vivo\",\n      \"pmids\": [\"29202476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In acetaminophen-induced liver injury, IL-11 secreted from APAP-damaged hepatocytes triggers an autocrine loop of NADPH oxidase 4 (NOX4)-dependent hepatocyte death downstream of mitochondrial dysfunction. Hepatocyte-specific Il11ra1 deletion or germline Il11 deletion protected mice from liver injury and was associated with reduced JNK and ERK activation and restored glutathione levels.\",\n      \"method\": \"Hepatocyte-specific and germline knockout mice, anti-IL11RA neutralizing antibody, NOX4 pathway analysis, GSH measurement, JNK/ERK western blotting\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type specific genetic knockout plus pharmacologic validation with defined molecular mechanism\",\n      \"pmids\": [\"34108253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 stimulates ERK activation in renal tubular epithelial cells (TECs) via p90RSK-mediated GSK3β inactivation, leading to SNAI1 upregulation, mesenchymal transition, and pro-inflammatory gene expression. TEC-specific deletion of Il11ra1 protected mice from renal injury-induced inflammation, fibrosis, and failure.\",\n      \"method\": \"TEC-specific Il11ra1 conditional knockout, ERK/p90RSK/GSK3β pathway analysis, SNAI1 expression, mouse AKI and CKD models, anti-IL11 antibody\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type specific knockout with defined signaling pathway and multiple disease models\",\n      \"pmids\": [\"36470928\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 binds the membrane-bound IL-11 receptor (IL-11R), which recruits a gp130 homodimer for classic signaling. The rhomboid intramembrane protease RHBDL2 (in addition to previously known ADAM10) cleaves IL-11R between Ala-370 and Ser-371, generating soluble IL-11R (sIL-11R) that enables IL-11 trans-signaling via gp130 homodimerization. RHBDL2 can cleave IL-11R in the early secretory pathway. The human mutation IL-11R-A370V prevents RHBDL2-mediated cleavage but not classic signaling.\",\n      \"method\": \"RHBDL2 overexpression/knockdown, cleavage site mutagenesis, sIL-11R bioactivity assay (STAT3 phosphorylation), subcellular localization studies, human mutation functional characterization\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — cleavage site identified by mutagenesis, biologically validated with trans-signaling assay, human mutation phenocopied\",\n      \"pmids\": [\"33566379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"A homozygous IL6ST variant (GP130 p.R281Q) causes selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, or CNTF signaling, demonstrating that a specific GP130 residue is required for IL-11 but not other IL-6 family cytokine signal transduction. Mice carrying the corresponding Il6st p.R279Q variant have facial synostosis and dental abnormalities phenocopying IL11RA deficiency.\",\n      \"method\": \"Transfected cell lines, primary patient-derived cells, genome-edited mouse model, cytokine panel signaling assays\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — selective signaling defect demonstrated in multiple cell systems and validated in mouse model\",\n      \"pmids\": [\"32566365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL11 stimulation of primary human fibroblasts (kidney, lung, skin) causes transient STAT3 phosphorylation but sustained ERK activation, and induces a proinflammatory secretome including IL8, IL6, MCP1, CCL20, CXCL1/5/6. IL11 induces IL33 expression (38-fold) via STAT3 (not ERK), establishing IL11 as pro-inflammatory in fibroblasts via the IL33 alarmin axis.\",\n      \"method\": \"RNA sequencing time course, proteomics/secretome analysis, STAT3 and MEK/ERK pharmacological inhibition, primary fibroblast cultures from three tissue types\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multi-organ fibroblast validation with orthogonal transcriptomic and proteomic readouts plus pathway-selective inhibition\",\n      \"pmids\": [\"36012165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In the bleomycin model of lung fibrosis, fibroblast-specific deletion of Il11ra1 (CKO) reduced pulmonary fibrosis, fibroblast ERK activation, chronic immune infiltrates, NF-kB phosphorylation, and pro-inflammatory gene activation, establishing that IL-11 signaling in fibroblasts drives both fibrosis and chronic inflammation in the lung.\",\n      \"method\": \"Fibroblast-specific loxP/Cre Il11ra1 knockout (CKO mice), bleomycin lung injury model, ERK/STAT3/NF-kB signaling analysis, neutralizing antibody comparison\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type specific genetic deletion with multiple molecular and histological readouts\",\n      \"pmids\": [\"32656894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In Marfan syndrome aortas, IL-11 is upregulated in vascular smooth muscle cells (VSMCs) and drives ERK-dependent collagen and MMP secretion, aortic dilatation, fibrosis, and inflammation. Genetic deletion of Il11ra1 or therapeutic anti-IL11RA antibody (X209) reduced aortic COL1A1, IL11, MMP2/9, and phospho-ERK expression and attenuated aortic pathology.\",\n      \"method\": \"Fbn1C1041G/+ mouse model crossed to Il11EGFP reporter and Il11ra1-/- strains; echocardiography; immunostaining; biochemical analyses; 20-week antibody treatment study\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis plus therapeutic antibody with longitudinal imaging in established disease model\",\n      \"pmids\": [\"35135328\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TGF-β1 induces IL-11 secretion from human dermal fibroblasts (HDFs); IL-11 stimulates ERK activation leading to HDF-to-myofibroblast transformation and extracellular matrix secretion via an autocrine loop that is independent of SMAD2/3 phosphorylation and STAT3 activity. Anti-IL11 antibody or IL11RA siRNA reduced TGFβ-induced HDF proliferation, matrix production, and migration, phenocopied by ERK inhibition.\",\n      \"method\": \"Gain- and loss-of-function in primary HDFs from SSc patients and controls; ERK/SMAD2/3/STAT3 western blotting; neutralizing antibody; siRNA knockdown; myofibroblast differentiation assay\",\n      \"journal\": \"Rheumatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary loss-of-function approaches with pathway specificity established by inhibitor panel\",\n      \"pmids\": [\"33590875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In pancreatic stellate cells (PSCs), IL-11 stimulation causes transient STAT3 phosphorylation and sustained ERK activation, leading to PSC-to-myofibroblast transformation. IL-6 stimulation caused sustained STAT3 but no ERK activation and no PSC transformation, demonstrating pathway specificity. TGFβ, CTGF, and PDGF induced IL-11 secretion from PSCs, and autocrine IL-11/ERK activity was required for their fibrogenic effects on PSCs.\",\n      \"method\": \"PSC culture, pharmacological inhibitors, cytokine panel comparison, anti-IL11RA neutralizing antibody, pancreatic duct ligation mouse model\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct pathway comparison (IL-11 vs IL-6) plus autocrine mechanism demonstrated with blocking antibody and in vivo model\",\n      \"pmids\": [\"35408908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-11 expressed specifically in fibroblasts places IL-11 activity upstream of IL-6 in fibrotic lung disease: Il11-/- mice have reduced Il1b, Timp1, Ccl2, and diminished IL6 expression both at baseline and after bleomycin injury. Il11-/- female mice are infertile. Unlike Il11ra1-/- mice, Il11-/- mice do not have craniosynostosis or altered long bone mass, indicating bone development anomalies are specifically associated with IL11RA but not IL11 itself.\",\n      \"method\": \"Il11 knockout mouse generation; comparison with Il11ra1-/- mice; bleomycin lung injury model; ERK/STAT3/NF-kB signaling; cytokine profiling; fertility assessment; bone phenotyping\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct genetic comparison of ligand vs receptor knockout with multiple phenotypic readouts establishing pathway hierarchy\",\n      \"pmids\": [\"34239012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HMGA2 transcription factor directly binds the IL11 promoter and activates its transcription, as demonstrated by chromatin immunoprecipitation-PCR and luciferase reporter assays. IL-11, as a direct downstream target of HMGA2, modulates cell migration and invasion through pSTAT3-dependent signaling.\",\n      \"method\": \"ChIP-PCR, luciferase reporter assay, HMGA2 overexpression/knockdown in colorectal cancer cells, STAT3 phosphorylation analysis\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding shown by ChIP plus functional rescue, single lab\",\n      \"pmids\": [\"26964871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The HIF target MAFF forms a heterodimer with BACH1 that directly transcriptionally activates IL11, leading to STAT3 signaling and breast cancer invasion/metastasis. Combined ChIP-seq and RNA-seq identified IL11 as a direct MAFF/BACH1 transcriptional target; IL11 inhibition reduced metastasis equivalently to MAFF inhibition.\",\n      \"method\": \"ChIP-seq, RNA-seq, siRNA knockdown, MAFF/BACH1 heterodimer characterization, metastasis assays in vivo\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq demonstrates direct binding plus functional equivalence of IL11 and MAFF inhibition\",\n      \"pmids\": [\"34262028\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cancer-associated fibroblasts promote chemoresistance in gastric cancer by secreting IL-11, which activates the IL-11/IL-11R/gp130/JAK/STAT3/Bcl2 anti-apoptosis pathway in cancer cells. JAK inhibitor combined with chemotherapy overcame resistance in vivo.\",\n      \"method\": \"CAF-cancer cell co-culture, flow cytometry, western blotting, MTT assay, xenograft mouse models, JAK inhibitor treatment\",\n      \"journal\": \"Cancer research and treatment\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — paracrine mechanism demonstrated with pathway inhibition and in vivo validation, single lab\",\n      \"pmids\": [\"29690750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-11 induces EMT in renal tubular epithelial cells via sequential activation of STAT3 then ERK1/2 signaling and upregulation of metadherin. Micheliolide (MCL) competitively inhibits IL-11 binding to IL-11Rα1, blocking STAT3 and ERK1/2-metadherin pathways and suppressing tubular EMT.\",\n      \"method\": \"UUO mouse model, siRNA knockdown of IL-11, competitive binding assay (MCL vs IL-11), STAT3/ERK1/2/metadherin pathway analysis, DMAMC pro-drug in vivo\",\n      \"journal\": \"American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — competitive binding assay identifies receptor interaction site, pathway sequencing by inhibitor studies, in vivo validation\",\n      \"pmids\": [\"37673330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In platinum-resistant ovarian cancer, elevated ROS sustain high IL-11 expression via FRA1-mediated transcriptional activation. Autocrine IL-11 then constitutively activates JAK2-STAT5 signaling to confer platinum resistance. JAK2 inhibition or anti-IL-11 antibody reversed resistance in vitro and in vivo.\",\n      \"method\": \"High-throughput combinational screen, genomic sequencing, FRA1 ChIP/reporter assay, JAK2 inhibitor (LY2784544), anti-IL-11 antibody, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway (ROS→FRA1→IL-11→JAK2-STAT5) established with ChIP, inhibitors, and in vivo validation\",\n      \"pmids\": [\"29662190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Breast cancer cells stimulate osteoblastic production of IL-11 (via PTHrP), which in turn enhances osteoblast PGE2 release; PGE2 then downregulates GM-CSF production by spleen cells to promote osteoclast formation. Neutralizing antibody to murine IL-11 or its receptor completely prevented osteoclastogenic activity of breast cancer-conditioned medium.\",\n      \"method\": \"Osteoblast-spleen cell co-culture system, ultrafiltration fractionation, neutralizing antibodies (PTHrP, murine IL-11, murine IL-11R, GM-CSF), COX inhibitor, recombinant GM-CSF\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway defined with specific neutralizing antibodies at each step\",\n      \"pmids\": [\"14999770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IL-11 regulates experimental autoimmune encephalomyelitis through two mechanisms: immunoregulation (reducing T cell effector cytokine production by modulating CD11c+ APC-mediated lymphocyte activation and reducing APC population size) and direct neuroprotection (reducing apoptosis and potentiating mitosis of oligodendrocyte progenitors). IL-11Rα-null mice displayed worsened disease.\",\n      \"method\": \"IL-11Rα knockout mice, EAE model, T cell/APC co-culture, oligodendrocyte progenitor cultures, IL-11 treatment in vivo\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout combined with cell-type-specific in vitro mechanistic studies\",\n      \"pmids\": [\"19734214\"],\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 activation downstream of IL-11/IL-11Rα/gp130 signaling. IL-11-conditioned MDSCs suppress T-cell proliferation via arginase-1 upregulation.\",\n      \"method\": \"PBMC culture with IL-11, flow cytometry, STAT3 phosphorylation assay, arginase-1 measurement, T-cell proliferation assay, immunohistochemistry of colorectal cancer tissue\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — STAT3 activation shown and functional MDSC suppression demonstrated, single lab\",\n      \"pmids\": [\"28781374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IL-11 induces NLRP3 inflammasome activation in monocytes; IL-11 stimulation of monocytes upregulates NFKB1, NLRP3, IL1B, and IL18 (scRNA-seq). IL-11R+ CSF monocytes from MS patients upregulate NLRP3 inflammasome-related genes and migratory genes (VEGFA/B). Anti-IL-11 mAb treatment 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+ cell sorting from CSF, αIL-11 mAb treatment in EAE mice, flow cytometry, immunohistochemistry\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — scRNA-seq mechanistic data combined with in vivo therapeutic validation\",\n      \"pmids\": [\"37339207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The SNP rs4252548 (R112H) in IL-11 does not impair receptor binding or STAT3 signaling but reduces thermal stability of the IL-11 protein. IL-11 R112H fails to support survival of osteoclast progenitor cells, attributable to the loss of positive charge at position 112.\",\n      \"method\": \"Crystal structure molecular replacement, recombinant protein expression, receptor binding affinity assay, STAT3 phosphorylation assay, thermal stability assay, osteoclast progenitor survival assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural analysis plus functional receptor binding and cell-based signaling validation\",\n      \"pmids\": [\"29237553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Sirt1 negatively regulates IL-11 transcription by deacetylating H3K9/14ac at the IL-11 promoter region (-871 to -724), which is also the major Smad2 binding region; this suppresses TGFβ1-induced IL-11/MEK/ERK signaling and senescence-associated pulmonary fibrosis.\",\n      \"method\": \"ChIP-seq/ChIP-PCR (H3K9/14ac, Smad2 binding), Sirt1 transgenic and Cyp27b1-/- mouse models, IL-11 promoter occupancy analysis, pulmonary function testing\",\n      \"journal\": \"Aging cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct histone modification mapping by ChIP-seq plus Smad2 co-occupancy at defined promoter region\",\n      \"pmids\": [\"35906886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WNT3a/β-catenin signaling in cardiac fibroblasts enhances TGFβ-induced IL-11 production and secretion via TAK1 phosphorylation (but not Smad pathway), potentiating myofibroblast transformation and collagen/fibronectin production. Anti-IL-11 antibody blocked the profibrotic effects of TGFβ+WNT3a co-stimulation.\",\n      \"method\": \"Human cardiac fibroblast culture, WNT3a/WNT5a/CHIR99021 stimulation, TAK1 phosphorylation western blotting, IL-11 ELISA, anti-IL-11 neutralizing antibody, β-catenin reporter assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway-specific analysis with TAK1 phosphorylation and neutralizing antibody in primary human cells, single lab\",\n      \"pmids\": [\"34576234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In skeletal myoblast preconditioning, IL-11 activates ERK1/2 and STAT3, and this is associated with upregulation of miR-21. miR-21 functions as a key regulator downstream of IL-11 in the ERK1/2-STAT3 signaling cascade; knockdown of miR-21, IL-11 siRNA, or ERK1/2 blockade each compromised the cytoprotective effect of preconditioning.\",\n      \"method\": \"Pharmacological preconditioning, IL-11 siRNA, ERK1/2 blocker, anti-miR-21, western blotting, in vivo cell survival assay in rat MI model\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pathway interventions in vitro with in vivo validation, single lab\",\n      \"pmids\": [\"20498256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IL-11 acts as a ligand of EGFR in addition to its canonical IL-11Rα/gp130 receptor, activating EGFR and downstream signaling to increase PDL1 expression in brain metastasis of EGFR-mutated NSCLC, promoting immune escape. Dual targeted inhibition of gp130 and EGFR suppressed brain metastasis growth in mice.\",\n      \"method\": \"Reactive astrocyte co-culture, IL-11 EGFR binding assay, PDL1 expression analysis, T-cell apoptosis assay, gp130 and EGFR inhibitor in vivo brain metastasis model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — novel receptor interaction with functional validation and in vivo data, single study\",\n      \"pmids\": [\"38696655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Autocrine IL-11 activates JAK1/STAT4 in docetaxel-resistant prostate cancer cells; pSTAT4 translocates to the nucleus, associates with CBP at the c-MYC promoter (ChIP-seq), and amplifies c-MYC transcriptional activity to drive resistance. Disruption of IL-11/IL-11RA autocrine loop or JAK1/STAT4 pathway restored docetaxel sensitivity.\",\n      \"method\": \"Single-cell secretion profiling, ChIP-seq (pSTAT4 genome-wide binding), co-immunoprecipitation (pSTAT4-CBP), luciferase reporter (c-MYC promoter), JAK1/STAT4 inhibitors, organoid and in vivo models\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — ChIP-seq identifies direct binding at c-MYC promoter, co-IP shows pSTAT4-CBP interaction, functional rescue with multiple interventions\",\n      \"pmids\": [\"38429845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IL-11 confers cytoprotection to human microvascular endothelial cells in a transplant alloinjury model by upregulating survivin expression; topical survivin antisense oligonucleotide largely abrogated the protective effect of IL-11 without affecting T cell activation or ICAM-1 expression.\",\n      \"method\": \"SCID/beige mouse human skin graft alloinjury model, intradermal IL-11 injection, survivin antisense oligonucleotide, immunohistochemistry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional rescue/knockdown experiment linking IL-11 to specific effector molecule in defined in vivo model\",\n      \"pmids\": [\"14734714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"In skeletal myoblast preconditioning studies, IL-11 is upstream of ERK1/2 activation; A1 adenosine receptor activation in renal proximal tubule cells induces IL-11 expression in an ERK-dependent manner, and IL-11 is required as a critical intermediary for A1AR-mediated induction of sphingosine kinase-1 and renal protection. IL-11 receptor-deficient mice lost A1AR-mediated renal protection.\",\n      \"method\": \"CCPA (A1AR agonist) treatment of HK-2 cells and mice, IL-11 neutralizing antibody, IL-11 receptor-deficient mice, renal proximal tubule-specific A1AR knockout, ERK inhibition, sphingosine kinase-1 assay\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (IL-11R-/-, A1AR KO) plus pharmacological dissection of the A1AR→ERK→IL-11→SphK1 axis\",\n      \"pmids\": [\"23813214\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-11 is a pleiotropic cytokine of the IL-6 family that signals through a membrane receptor complex of IL-11Rα and gp130, activating ERK (the dominant pro-fibrotic pathway), STAT3 (context-dependent), and JAK kinases; downstream of ERK it phosphorylates p90RSK, inactivates LKB1/AMPK, and activates mTOR to drive collagen synthesis via an EPRS-regulated ribosome-stalling mechanism, while autocrine IL-11/ERK signaling in fibroblasts is required for TGFβ1-induced fibrogenesis across multiple organs, and IL-11 can also engage EGFR as an alternative receptor and undergo ectodomain shedding by ADAM10 or RHBDL2 to generate soluble IL-11R that enables trans-signaling through gp130 homodimerization.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IL-11 is a pleiotropic IL-6 family cytokine that signals through an IL-11Rα/gp130 receptor complex to activate ERK, JAK/STAT, and downstream metabolic effectors, functioning as a central mediator of organ fibrosis, tissue injury responses, immune modulation, and aging-associated metabolic decline. In fibroblasts and epithelial cells, TGF-β1 induces IL-11 secretion, which engages an autocrine ERK-dependent loop—via p90RSK-mediated LKB1 inactivation, AMPK suppression, and mTOR activation—to drive collagen synthesis through an EPRS-regulated ribosome-stalling mechanism and myofibroblast transformation across heart, lung, kidney, liver, skin, and pancreas [PMID:29160304, PMID:34651016, PMID:35992082]. IL-11 trans-signaling is enabled by ectodomain shedding of IL-11Rα by RHBDL2 or ADAM10, generating soluble IL-11R that activates gp130 homodimers on cells lacking membrane IL-11Rα [PMID:33566379]; a specific gp130 residue (R281) is selectively required for IL-11 but not other IL-6-family cytokine signaling [PMID:32566365]. Homozygous loss-of-function mutations in IL11RA cause craniosynostosis and dental anomalies in humans [PMID:21741611], while genetic deletion or antibody neutralization of IL-11 in aged mice extends lifespan by ~22–25% through relief of the ERK–AMPK–mTORC1 metabolic axis [PMID:39020175].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Determination of IL11 gene structure and chromosomal location established the genomic framework for subsequent promoter and regulatory studies.\",\n      \"evidence\": \"Genomic cloning, in situ hybridization, and sequence analysis mapped IL11 to 19q13.3–q13.4 with five exons and IL-1-responsive regulatory elements\",\n      \"pmids\": [\"1386338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Promoter elements not functionally validated at this stage\", \"No information on tissue-specific transcription factors controlling IL11\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Establishing that IL-11 signals through gp130 resolved how a distinct cytokine converges on the same signal transducer as IL-6, defining the shared receptor architecture of the IL-6 family.\",\n      \"evidence\": \"Anti-gp130 antibodies abolished IL-11-induced proliferation, tyrosine phosphorylation, and junB expression in TF-1 cells, while anti-IL-6R had no effect on IL-11 signaling\",\n      \"pmids\": [\"8360477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structure of the IL-11Rα/gp130 signaling complex not determined\", \"Downstream kinase cascades not yet mapped\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of JAK, MAPK, and p90RSK as IL-11-activated kinases, with p90RSK as the critical mediator of primary response gene induction, revealed that IL-11 signals through non-STAT pathways with functional importance.\",\n      \"evidence\": \"Kinase activation assays and H7 inhibitor studies in mouse preadipocytes showed p90RSK is required for junB, tis11, and tis8 expression; STAT91 tyrosine phosphorylation was insufficient alone\",\n      \"pmids\": [\"7545369\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream substrates of p90RSK in IL-11 context not identified\", \"Single cell system (preadipocytes)\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Discovery of IL-11's role in osteoclastogenesis and endothelial cytoprotection extended its known biology beyond hematopoiesis to bone remodeling and vascular protection.\",\n      \"evidence\": \"Neutralizing anti-IL-11/IL-11R antibodies blocked breast cancer-induced osteoclast formation via a PTHrP→IL-11→PGE2→GM-CSF axis; separately, IL-11 upregulated survivin to protect endothelial cells in transplant alloinjury\",\n      \"pmids\": [\"14999770\", \"14734714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Survivin mechanism not fully resolved—single antisense approach\", \"Direct IL-11 action on osteoclast precursors versus indirect (osteoblast-mediated) effects not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstration that IL-11 exerts dual immunoregulatory and neuroprotective functions in EAE established it as an anti-inflammatory cytokine in CNS autoimmunity.\",\n      \"evidence\": \"IL-11Rα-null mice had worsened EAE; IL-11 reduced T cell effector cytokines via APC modulation and directly promoted oligodendrocyte progenitor survival\",\n      \"pmids\": [\"19734214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific contribution (APC vs oligodendrocyte) not genetically separated\", \"Whether IL-11 is protective or pathogenic in other neuroinflammatory contexts unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Human genetic evidence that IL11RA loss-of-function causes craniosynostosis and dental anomalies established IL-11 signaling as essential for craniofacial and dental development.\",\n      \"evidence\": \"Homozygosity mapping identified IL11RA mutations; the p.Arg296Trp mutation abolished IL-11 signaling in transfection assays; Il11ra-null mice phenocopied the human syndrome\",\n      \"pmids\": [\"21741611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of IL-11 in suture biology not identified\", \"Whether IL-11 itself (vs other IL-11Rα ligands) is the relevant signal in vivo not distinguished until later\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstration that cardiac IL-11 protection against ischemia/reperfusion requires STAT3 established a tissue-protective signaling axis distinct from later fibrotic mechanisms.\",\n      \"evidence\": \"Cardiac-specific STAT3 conditional knockout mice lost IL-11-mediated cardioprotection and failed to suppress ROS after I/R\",\n      \"pmids\": [\"22707562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ERK also contributes to cardioprotection not tested\", \"Acute protective role later reinterpreted in light of chronic fibrotic signaling—reconciliation incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery that IL11 is a hypoxia/HIF-1-inducible gene with autocrine tumor-promoting activity linked IL-11 to the cancer microenvironment; separately, IL-11 was identified as a required intermediary in A1AR-mediated renal protection.\",\n      \"evidence\": \"VHL manipulation and promoter dissection showed HIF-1/AP-1 cooperation at IL11 promoter; IL-11 knockdown abolished hypoxia-driven anchorage-independent growth and xenograft growth. In kidney, IL-11R-deficient mice lost A1AR-mediated protection via an ERK→IL-11→SphK1 axis\",\n      \"pmids\": [\"23549086\", \"23813214\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of classic vs trans-signaling in tumor microenvironment unknown\", \"Whether renal protective and fibrotic IL-11 effects use the same downstream signaling not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The paradigm-shifting discovery that IL-11 is the dominant TGF-β1 target in fibroblasts and drives organ fibrosis via autocrine ERK signaling reframed IL-11 from a hematopoietic cytokine to a master fibrogenic factor.\",\n      \"evidence\": \"Integrated imaging-genomics in primary human fibroblasts; fibroblast-specific Il11 transgenics caused heart/kidney fibrosis; Il11ra1 deletion protected against fibrosis; ERK pathway was required\",\n      \"pmids\": [\"29160304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ERK selectively drives collagen translation not yet elucidated\", \"Whether STAT3 activation is an artifact of species-mismatched recombinant IL-11 not yet formally tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A specific gp130 residue (R281) was shown to be selectively required for IL-11 signaling, and fibroblast-specific IL-11Rα deletion proved sufficient to prevent lung fibrosis and chronic inflammation, demonstrating cell-autonomous fibroblast IL-11 signaling as the driver.\",\n      \"evidence\": \"GP130 p.R281Q human variant and mouse Il6st p.R279Q knock-in abolished IL-11 but not IL-6/OSM/LIF signaling, phenocopying IL11RA deficiency; fibroblast-specific Il11ra1 CKO reduced bleomycin-induced fibrosis, ERK activation, and NF-κB phosphorylation\",\n      \"pmids\": [\"32566365\", \"32656894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for gp130 R281 selectivity not determined\", \"Whether gp130 homodimer engagement differs between classic and trans-signaling not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mechanistic dissection revealed that IL-11-induced ERK activates mTOR/P70RSK and collagen synthesis via EPRS-regulated ribosome stalling, while STAT3 activation causes ER stress; concurrently, RHBDL2 was identified as a second IL-11Rα sheddase enabling trans-signaling, and IL-11 was shown to drive fibrosis, injury, and inflammation across kidney, liver, skin, lung, and vasculature through organ-specific ERK-dependent programs.\",\n      \"evidence\": \"ERK/STAT3/mTOR inhibitor panels in Il11ra1-KO fibroblasts established ERK–mTOR–EPRS axis for collagen synthesis; RHBDL2 cleavage site (A370–S371) identified by mutagenesis; hepatocyte-specific and TEC-specific Il11ra1 deletions protected against APAP liver injury (NOX4/JNK-dependent) and kidney injury (p90RSK/GSK3β/SNAI1-dependent); Il11-KO mice showed reduced IL-6 and pro-inflammatory cytokines and female infertility\",\n      \"pmids\": [\"34651016\", \"33566379\", \"34108253\", \"36470928\", \"34239012\", \"35135328\", \"33590875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EPRS ribosome stalling selectively controls collagen mRNAs not structurally resolved\", \"Relative contribution of classic versus trans-signaling in each organ not quantified\", \"Discrepancy between Il11-KO (no craniosynostosis) and Il11ra1-KO (craniosynostosis) suggests IL-11Rα has IL-11-independent roles not yet defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identification of ERK/P90RSK-mediated LKB1 phosphorylation (S325, S428) as the mechanism linking IL-11 to AMPK inhibition and mTOR activation unified the metabolic and fibrogenic arms of IL-11 signaling.\",\n      \"evidence\": \"Phosphoproteomics identified LKB1 phosphorylation sites; site-specific LKB1 mutagenesis blocked IL-11 effects; metformin-stimulated AMPK activation inhibited IL-11 phenotypes in fatty liver disease models\",\n      \"pmids\": [\"35992082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether LKB1 inactivation is the sole link to mTOR or parallel pathways exist\", \"Tissue-specificity of LKB1 phosphorylation by IL-11 not systematically assessed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Epigenetic regulation of IL11 transcription was defined: Sirt1 deacetylates H3K9/14ac at the IL11 promoter (overlapping the Smad2 binding region) to suppress TGF-β1-induced IL-11 expression, connecting aging-associated epigenetic changes to fibrosis.\",\n      \"evidence\": \"ChIP-seq/ChIP-PCR mapped H3K9/14ac and Smad2 co-occupancy at IL11 promoter (-871 to -724); Sirt1 transgenic mice resisted pulmonary fibrosis\",\n      \"pmids\": [\"35906886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other sirtuins or HDACs regulate IL11 not tested\", \"Chromatin context in non-fibroblast cell types unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genetic deletion or antibody neutralization of IL-11 in aged mice extended lifespan by ~22–25%, establishing the ERK–AMPK–mTORC1 axis driven by IL-11 as a determinant of mammalian aging.\",\n      \"evidence\": \"Il11-/- and Il11ra1-/- mice showed improved metabolic parameters; anti-IL-11 antibody treatment from 75 weeks extended median lifespan in both sexes\",\n      \"pmids\": [\"39020175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue sources of IL-11 driving systemic aging not resolved\", \"Whether lifespan extension reflects fibrosis reduction, metabolic improvement, or both\", \"Human translational relevance not yet tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"IL-11 was identified as an EGFR ligand, expanding the receptor repertoire beyond IL-11Rα/gp130, and an autocrine IL-11/JAK1/STAT4/c-MYC axis was found to drive chemoresistance in prostate cancer.\",\n      \"evidence\": \"IL-11 binding to EGFR demonstrated in brain metastasis model, with dual gp130/EGFR inhibition suppressing growth; ChIP-seq showed pSTAT4 binding at c-MYC promoter with CBP co-IP in docetaxel-resistant prostate cancer\",\n      \"pmids\": [\"38696655\", \"38429845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"EGFR interaction is from a single study and awaits independent confirmation\", \"STAT4 pathway in IL-11 signaling is novel and not yet replicated across systems\", \"Structural basis of IL-11/EGFR interaction unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: the structural basis of the IL-11/IL-11Rα/gp130 hexameric complex at atomic resolution, the mechanism by which EPRS-dependent ribosome stalling selectively controls collagen translation, the relative contribution of classic versus trans-signaling in each disease context, reconciliation of IL-11's acute protective versus chronic pathogenic roles in the same organs, and the identity of the dominant cellular sources of IL-11 driving systemic aging.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of the complete IL-11 signaling complex\", \"EPRS ribosome stalling selectivity mechanism unresolved\", \"Classic vs trans-signaling contributions not quantified in vivo\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 4, 7, 8, 13, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 9, 10, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [4, 15, 17, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 8, 9, 14, 16]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [29, 30, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 12, 25, 27, 37]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [4, 18, 19, 20, 21]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [13, 38]}\n    ],\n    \"complexes\": [\n      \"IL-11/IL-11Rα/gp130 signaling complex\"\n    ],\n    \"partners\": [\n      \"IL6ST\",\n      \"IL11RA\",\n      \"STAT3\",\n      \"MAPK1\",\n      \"RPS6KA1\",\n      \"STK11\",\n      \"EGFR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}