{"gene":"IL6R","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2013,"finding":"The non-synonymous IL6R variant Asp358Ala (rs2228145) increases transcription of the soluble IL6R isoform but not the membrane-bound isoform, reduces surface expression of IL-6R on CD4+ T cells and monocytes (up to 28% reduction per allele), and consequently impairs IL-6-induced STAT3 and STAT1 phosphorylation, demonstrating that this variant shifts the balance from classical membrane-bound IL-6R signaling toward trans-signaling.","method":"Flow cytometry of PBMCs from 128 volunteers, STAT3/STAT1 phosphorylation assays, allele-specific expression analysis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional assays (surface expression + downstream signaling) in a large genotyped cohort with multiple orthogonal methods","pmids":["23593036"],"is_preprint":false},{"year":2013,"finding":"The IL6R Asp358Ala variant (rs2228145) is associated with elevated serum soluble IL-6R levels (~34.6% increase per copy of 358Ala allele), and homozygous carriers show approximately 2-fold higher soluble IL-6R. Elevated soluble IL-6R is also higher in atopic dermatitis patients versus controls, linking the variant to altered trans-signaling.","method":"ELISA measurement of serum sIL-6R; GWAS meta-analysis across 7 study populations with 7130 AD patients","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — large epidemiological validation with ELISA functional readout, single lab for mechanistic component","pmids":["23582566"],"is_preprint":false},{"year":2017,"finding":"The IL6R p.D358A allele leads to increased proteolytic shedding of membrane-bound IL-6R; peptides containing A358 are more susceptible to cleavage by ADAM10 and ADAM17 compared to D358 peptides, providing a molecular mechanism for the genotype-dependent increase in circulating soluble IL-6R.","method":"In vitro cleavage assays with recombinant ADAM10 and ADAM17 on IL-6R peptide variants","journal":"Journal of Alzheimer's disease : JAD","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay with mutagenesis, single lab, single method","pmids":["28106546"],"is_preprint":false},{"year":2002,"finding":"In human osteoblasts, membrane-bound IL-6R (gp80) is nonfunctional and cannot activate gp130 signaling; only after shedding into soluble form (sIL-6R) via a protein kinase C-dependent mechanism does the IL-6/sIL-6R complex induce rapid tyrosine phosphorylation of gp130. PKC inhibitors block both spontaneous and PMA-induced IL-6R shedding and prevent gp130 activation.","method":"Immunoprecipitation, flow cytometry, tyrosine phosphorylation assays, neutralizing antibodies to sIL-6R and gp130, PKC inhibitors in osteoblast cell lines and primary osteoblasts","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with neutralizing antibodies and inhibitors, multiple osteoblast cell lines and primary cells, multiple orthogonal methods","pmids":["11884403"],"is_preprint":false},{"year":1999,"finding":"Natural soluble IL-6R (sIL-6R, gp80) and natural soluble gp130 (sgp130) interact directly in the absence of IL-6 with a Kd of 2.8 nM as measured by surface plasmon resonance; this binary complex is unable to bind IL-6, suggesting that circulating sgp130 can inhibit IL-6 trans-signaling by sequestering sIL-6R.","method":"Surface plasmon resonance (Biacore) using proteins purified from human plasma","journal":"European cytokine network","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro binding kinetics with purified natural proteins, single lab, single method","pmids":["10210772"],"is_preprint":false},{"year":2006,"finding":"Human herpesvirus 8 vIL-6 can signal through gp130 in the absence of gp80 (IL-6R alpha); chimeric and point-mutant analysis showed that the B helix of vIL-6 is absolutely required for gp80-independent signaling, and gp80 was found to stabilize vIL-6-induced gp130:gp130 signaling complexes even when not required for signaling initiation.","method":"Site-directed mutagenesis, chimeric IL-6 constructs, co-immunoprecipitation, signaling assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with functional reconstitution and co-IP, multiple orthogonal methods in single rigorous study","pmids":["16973585"],"is_preprint":false},{"year":2014,"finding":"IL-6 activates STAT3, which directly represses the MIR34A gene via a conserved STAT3-binding site. miR-34a in turn directly targets IL-6R mRNA (both membrane-bound form). This creates an IL-6R/STAT3/miR-34a positive feedback loop that is required for IL-6-induced EMT, invasion, and metastasis in colorectal cancer cells. p53 activation disrupts this loop via miR-34a-dependent IL-6R downregulation.","method":"Luciferase reporter assays, miR-34a gain/loss of function, STAT3 ChIP, CRC cell invasion assays, Mir34a-deficient mouse model of colitis-associated cancer","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter assays, genetic mouse model, human tumor data), replicated across multiple cancer cell lines","pmids":["24642471"],"is_preprint":false},{"year":2015,"finding":"miR-34a directly targets and represses both the membrane-bound IL-6R mRNA and the mRNA encoding soluble IL-6R (sIL-6R); ectopic miR-34a expression reduced sIL-6R protein concentration in conditioned media of CRC cell lines, extending the IL-6R/STAT3/miR-34a feedback loop to include trans-signaling.","method":"Luciferase reporter assay for sIL-6R 3'UTR targeting, ELISA of conditioned media, Western blot","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR validation plus protein level readout, same lab as PMID 24642471 but adds sIL-6R as new target","pmids":["26091352"],"is_preprint":false},{"year":2006,"finding":"CD4+CD25- T cells express both CD126 (IL-6R alpha) and CD130 (gp130) and show STAT3 phosphorylation after IL-6 or hyper-IL-6 stimulation, whereas CD4+CD25high Treg cells express CD126 but little CD130 and show markedly less STAT3 phosphorylation; downmodulation of CD126 and CD130 after ligand binding occurred on conventional T cells but not Tregs. MAPK ERK1/2 was not activated by CD130 dimerization.","method":"Flow cytometry, phospho-STAT3 and phospho-ERK1/2 intracellular staining, surface receptor modulation assays","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct functional signaling readout tied to receptor expression across defined T cell subsets, multiple methods, single lab","pmids":["16540526"],"is_preprint":false},{"year":1995,"finding":"Oncostatin M (OSM) upregulates IL-6R (gp80) mRNA approximately 2-fold in rat hepatoma cells, an effect additive with dexamethasone, whereas IL-1 inhibits dexamethasone-mediated IL-6R mRNA induction and induces a smaller IL-6R transcript lacking transmembrane and cytoplasmic domains, suggesting alternate splicing to generate a soluble form. gp130 expression was not substantially regulated under the same conditions.","method":"Northern blot / steady-state mRNA analysis of cytokine-stimulated H-35 rat hepatoma cells","journal":"Cytokine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple cytokine conditions with transcript-level analysis; two independent observations (OSM induction and IL-1-induced splice variant), single lab","pmids":["8580365"],"is_preprint":false},{"year":2019,"finding":"In multiple myeloma cells, metformin specifically decreases IL-6R expression via AMPK, mTOR, and miR-34a pathways, thereby reducing IL-6 signaling.","method":"Western blot, qPCR, AMPK/mTOR pathway inhibitors and activators, miR-34a modulation in myeloma cell lines","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway inhibitors and molecular readouts in a single-lab study establish the AMPK/mTOR/miR-34a axis controlling IL-6R expression","pmids":["30988378"],"is_preprint":false},{"year":2019,"finding":"IL-6R (CD126) and ADAR1-P150 cooperate to hyperactivate the STAT3 pathway in multiple myeloma. High IL-6R expression confers hypersensitivity to IL-6 binding, while ADAR1-P150 is a direct STAT3 transcriptional target that in turn physically interacts with and stabilizes STAT3, forming a feedforward loop. Concomitant knockdown of both IL-6R and ADAR1 impeded IL-6-induced STAT3 pathway activation more than either alone.","method":"siRNA knockdown, co-immunoprecipitation, transcriptional reporter assays, IL-6 stimulation assays in myeloma cell lines","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus double knockdown epistasis and IL-6 stimulation, single lab, multiple orthogonal methods","pmids":["31413087"],"is_preprint":false},{"year":2019,"finding":"VEGFR2 auto-phosphorylation and downstream Src, ERK, AKT, mTOR, and STAT3 activation in endothelial cells requires concurrent IL-6R-gp130 and C3ar1/C5ar1 co-signaling; blockade of either IL-6R or C3ar1/C5ar1 completely abolished VEGFR2 signaling and EC cell cycle entry. Co-immunoprecipitation and BRET assays demonstrated physical interaction among VEGFR2, IL-6R-gp130, and C3ar1/C5ar1.","method":"Co-immunoprecipitation, BRET assay, confocal microscopy, ligand pulldown, receptor blockade, in vivo retinal angiogenesis model","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal interaction assays (Co-IP, BRET, pulldown) plus functional rescue in vitro and in vivo, single rigorous study","pmids":["30765465"],"is_preprint":false},{"year":2016,"finding":"In intestinal epithelial cells, classical IL-6 signaling through membrane-bound IL-6R (IL-6RΔIEC knockout mice) is dispensable for intestinal repair and does not protect against DSS-induced colitis or inflammation-induced carcinogenesis, while primary non-malignant intestinal organoids do not respond to IL-6 classic signaling; IL-6 STAT3 activation was only observed in colonic cancer cell lines.","method":"Intestinal epithelial-specific IL-6R knockout mice (IL-6RΔIEC), DSS colitis model, azoxymethane-DSS carcinogenesis model, intestinal organoid culture, STAT3 phosphorylation assay","journal":"Oncogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO with two independent in vivo disease models and organoid validation; negative finding that classic IL-6R signaling is dispensable for epithelial repair","pmids":["27869785"],"is_preprint":false},{"year":2016,"finding":"Circulating soluble IL-6R (sIL-6R) enters inflamed tissue from the circulation in an ADAM17-independent manner to enable IL-6 trans-signaling and mononuclear cell recruitment; using ADAM17 hypomorphic mice with ~5% normal ADAM17 levels, local ADAM17-mediated shedding within the air pouch was shown not to be the source of sIL-6R driving trans-signaling in this model.","method":"ADAM17 hypomorphic mouse model, murine air pouch inflammation model, cytokine and cell infiltration measurements","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic hypomorph model with defined cellular readout; single lab but rigorous genetic approach","pmids":["27698010"],"is_preprint":false},{"year":2005,"finding":"A peptide (S7) identified by phage display library screening specifically binds to the IL-6R alpha chain (gp80) and blocks IL-6 binding to IL-6R alpha in a dose-dependent manner, inhibits IL-6-mediated survival signaling, VEGF-A expression, and angiogenesis in cancer cells in vitro, and suppresses IL-6-induced cervical tumor growth in vivo.","method":"Phage display, competitive binding assay, cell signaling assays, VEGF-A ELISA, SCID mouse xenograft","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding competition assay plus functional in vitro and in vivo validation, single lab","pmids":["15930303"],"is_preprint":false},{"year":1994,"finding":"Epitope mapping of human IL-6R (gp80) using 7 monoclonal antibodies identified four distinct epitopes; two epitopes (recognized by M37, M113, M139, M164 group and M195) are involved in IL-6 binding and antibodies against them inhibit IL-6 binding and IL-6-dependent cell proliferation, while two other epitopes (M91, M182) do not participate in IL-6 binding, though M182 still interferes with the proliferative response.","method":"ELISA, FACS, Western blot, cross-blocking assays, Biacore surface plasmon resonance, IL-6-dependent cell proliferation assay","journal":"European cytokine network","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal epitope mapping methods including SPR, single lab","pmids":["7524715"],"is_preprint":false},{"year":2000,"finding":"CD126 (IL-6R alpha chain) is expressed on neoplastic plasma cells from ~90% of myeloma patients and MGUS but is undetectable on normal plasma cells; expression is highest on VLA-5- immature myeloma cells and is not induced by bone marrow stromal cells, as neoplastic cells show higher CD126 levels than normal plasma cells from the same marrow.","method":"4-color flow cytometry of bone marrow samples from 93 myeloma, 66 MGUS/plasmacytoma, and 11 normal subjects","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct flow cytometry with large patient cohort and internal controls from same marrow, single lab","pmids":["11090073"],"is_preprint":false},{"year":2008,"finding":"Serum soluble IL-6R (sIL-6R) levels increased three-fold during HgCl2-induced acute kidney injury in mice; stimulation with an IL-6/sIL-6R fusion protein activated STAT3 in renal tubular epithelium (which lacks membrane IL-6R) and prevented AKI, suggesting IL-6 trans-signaling through sIL-6R is protective in kidney injury and mediates its effect partly through reduction of lipid peroxidation.","method":"IL-6-deficient mouse model, neutrophil depletion, IL-6/sIL-6R fusion protein administration, STAT3 immunohistochemistry, lipid peroxidation assay","journal":"Journal of the American Society of Nephrology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout and pharmacological reconstitution with functional cellular readout, single lab","pmids":["18337485"],"is_preprint":false},{"year":2023,"finding":"Human forebrain neural progenitor cells (NPCs) did not respond to IL-6 stimulation due to absence of IL-6R expression and no soluble IL-6Ra secretion, whereas hiPSC-derived microglia-like cells expressing canonical IL-6Ra showed STAT3 phosphorylation, upregulation of IL6, JMJD3 and IL10, and increased motility upon acute IL-6 exposure.","method":"hiPSC-derived microglia and NPC cultures, STAT3 phosphorylation assay, bulk RNAseq, cytokine multiplex, flow cytometry for IL-6R expression","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in defined human cell models, single lab; cell-type specificity of IL-6R signaling directly established","pmids":["36781081"],"is_preprint":false},{"year":2020,"finding":"CD4+Foxp3+ Treg cells with low/negative CD126 (IL-6R alpha) expression are functionally superior and more stable than CD126Hi Treg cells, even in the presence of IL-6 and inflammation; CD126Lo/- Tregs successfully treated colitis and collagen-induced arthritis in mice, whereas CD126Hi Tregs failed. CD126 expression on Treg cells positively correlated with RA severity.","method":"In vitro stability assays with IL-6, adoptive transfer in colitis and CIA mouse models, flow cytometry","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo functional data with defined cell subsets, multiple disease models, single lab","pmids":["32738192"],"is_preprint":false},{"year":2015,"finding":"ALDH-high cancer stem-like cells in endometrial cancer show upregulated IL-6R subunits CD126 and GP130; targeted inhibition of IL-6R and its downstream effectors JAK1 and STAT3 dramatically reduced tumor cell growth and diminished the ALDHhi/CD126+ stem-like component.","method":"Flow cytometry for ALDH activity and CD126/GP130 expression, pharmacological IL-6R/JAK1/STAT3 inhibition, organoid and xenograft assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — expression analysis linked to functional inhibition with in vivo validation, single lab","pmids":["26130650"],"is_preprint":false},{"year":2017,"finding":"IL-6 activates STAT3, which directly represses miR-204 via a conserved STAT3-binding site; loss of miR-204 derepresses IL-6R expression, forming an IL-6R/STAT3/miR-204 positive feedback loop that drives cisplatin resistance in epithelial ovarian cancer cells; exogenous miR-204 blocked this circuit and enhanced cisplatin sensitivity in vitro and in vivo.","method":"Luciferase reporter, STAT3 ChIP, miR-204 gain/loss of function, in vitro and in vivo cisplatin sensitivity assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus in vivo validation, single lab; analogous loop to CRC miR-34a finding but independent study","pmids":["28388577"],"is_preprint":false},{"year":2021,"finding":"CD126 (IL-6R) is broadly expressed on multiple hematologic and solid tumor types; CAR-T cells targeting CD126 kill tumor cells in an antigen-specific manner proportional to CD126 expression levels; soluble CD126 does not interfere with CAR-T cell killing; and binding of sIL-6R by CD126 CAR-T cells may mitigate cytokine release syndrome (evidenced by lower murine SAA-3 levels).","method":"Flow cytometry for CD126 expression, CAR-T killing assays, myeloma and prostate xenograft mouse models","journal":"Blood cancer journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — antigen-specific killing validated in vitro and in two xenograft models, single lab","pmids":["33414408"],"is_preprint":false}],"current_model":"IL-6R (CD126/gp80) is the ligand-binding alpha-chain of the IL-6 receptor complex that, upon IL-6 binding, recruits the signal-transducing subunit gp130 to activate JAK/STAT3 and MAPK signaling; membrane-bound IL-6R mediates classical signaling in cells expressing both subunits, while proteolytic shedding of IL-6R by ADAM10/ADAM17 (facilitated by the disease-associated Asp358Ala variant) generates soluble IL-6R (sIL-6R) that enables IL-6 trans-signaling in cells lacking membrane IL-6R, with sgp130 able to sequester sIL-6R to dampen trans-signaling; IL-6R expression and signaling are regulated by miRNAs (including miR-34a, miR-204), cytokines (OSM, IL-1), and AMPK/mTOR, and IL-6R participates in oncogenic feedback loops (IL-6R/STAT3/miR-34a) that promote EMT, invasion, and drug resistance in multiple cancers."},"narrative":{"mechanistic_narrative":"IL6R encodes the ligand-binding alpha-chain (gp80/CD126) of the interleukin-6 receptor, whose engagement of IL-6 governs activation of the signal-transducing subunit gp130 and downstream STAT3 phosphorylation across immune, epithelial, and tumor cells [PMID:11884403, PMID:16540526]. Receptor function is partitioned between membrane-bound classical signaling and trans-signaling driven by a soluble IL-6R ectodomain (sIL-6R) generated by proteolytic shedding through ADAM10 and ADAM17; the IL-6/sIL-6R complex activates gp130 in cells lacking membrane IL-6R, while soluble gp130 directly binds sIL-6R (Kd ~2.8 nM) to sequester it and dampen trans-signaling [PMID:28106546, PMID:10210772]. In some cell types membrane IL-6R alone is insufficient: in osteoblasts only the shed soluble form, released by a PKC-dependent mechanism, activates gp130, and classical IL-6R signaling is dispensable for intestinal epithelial repair and inflammation-driven carcinogenesis [PMID:11884403, PMID:27869785]. The common Asp358Ala (rs2228145) variant shifts this balance by increasing soluble-isoform transcription and enhancing ADAM10/ADAM17 cleavage of the receptor, lowering surface IL-6R and raising circulating sIL-6R [PMID:23593036, PMID:23582566, PMID:28106546]. IL-6R sits in oncogenic STAT3 feedback circuits in which STAT3 represses miR-34a and miR-204, both of which directly target IL-6R mRNA, creating positive feedback loops that promote EMT, invasion, drug resistance, and cancer stemness [PMID:24642471, PMID:28388577, PMID:26130650]. Receptor abundance is further controlled by an AMPK/mTOR/miR-34a axis, and CD126 is selectively overexpressed on malignant plasma cells, making it both a signaling determinant and a therapeutic target via blocking peptides and CAR-T cells [PMID:30988378, PMID:11090073, PMID:33414408].","teleology":[{"year":1994,"claim":"Defining which surfaces of IL-6R mediate ligand binding was needed to map the functional receptor architecture; epitope mapping resolved distinct ligand-binding versus non-binding regions of gp80.","evidence":"Monoclonal antibody epitope mapping with ELISA, FACS, cross-blocking, SPR and proliferation assays","pmids":["7524715"],"confidence":"Medium","gaps":["No atomic structure of the IL-6/IL-6R/gp130 complex established here","Did not address gp130 recruitment geometry"]},{"year":1995,"claim":"It was unknown how IL-6R expression is transcriptionally regulated by other cytokines; OSM and IL-1 were shown to modulate IL-6R mRNA and generate a transmembrane-lacking transcript, hinting at a soluble form via splicing.","evidence":"Northern blot mRNA analysis of cytokine-stimulated rat hepatoma cells","pmids":["8580365"],"confidence":"Medium","gaps":["Splice variant inferred from transcript size, not sequenced","Protein-level confirmation of soluble form absent"]},{"year":1999,"claim":"How soluble gp130 might restrain trans-signaling was unclear; direct binding measurements showed sgp130 binds sIL-6R in the absence of IL-6, establishing a sequestration mechanism.","evidence":"Surface plasmon resonance with proteins purified from human plasma","pmids":["10210772"],"confidence":"Medium","gaps":["Single in vitro binding method","Physiological buffering capacity in vivo not quantified"]},{"year":2002,"claim":"Whether membrane IL-6R is universally functional was untested; in osteoblasts membrane gp80 was nonfunctional and only PKC-dependent shedding to sIL-6R enabled gp130 activation.","evidence":"Immunoprecipitation, neutralizing antibodies, PKC inhibitors in osteoblast lines and primary cells","pmids":["11884403"],"confidence":"High","gaps":["PKC-targeted protease not identified","Generalizability beyond osteoblasts not addressed"]},{"year":2006,"claim":"The roles of gp80 in gp130 signaling complexes were probed using viral IL-6; vIL-6 signals through gp130 without gp80, yet gp80 stabilizes the gp130 signaling complex, clarifying gp80's structural contribution.","evidence":"Site-directed mutagenesis, chimeric constructs, co-IP and signaling assays","pmids":["16973585"],"confidence":"High","gaps":["Relevance of vIL-6 mechanism to human IL-6 signaling limited","Stoichiometry of stabilized complex not resolved"]},{"year":2006,"claim":"Cell-type-specific IL-6 responsiveness was unexplained; differential CD126/CD130 expression across T-cell subsets dictated STAT3 activation, with Tregs poorly responsive due to low gp130.","evidence":"Flow cytometry and phospho-STAT3/ERK staining across T-cell subsets","pmids":["16540526"],"confidence":"Medium","gaps":["Mechanism of Treg-specific receptor regulation not defined","Functional consequence in vivo not tested here"]},{"year":2008,"claim":"Whether trans-signaling is purely pathogenic was open; in kidney injury IL-6/sIL-6R trans-signaling activated STAT3 in tubular epithelium lacking membrane IL-6R and was protective.","evidence":"IL-6-deficient mice, IL-6/sIL-6R fusion protein, STAT3 IHC, lipid peroxidation assays","pmids":["18337485"],"confidence":"Medium","gaps":["Direct source of endogenous sIL-6R not defined","Protective mechanism beyond lipid peroxidation incomplete"]},{"year":2013,"claim":"The functional consequence of the Asp358Ala variant was unknown; it was shown to favor soluble isoform transcription, reduce surface IL-6R, and impair classical STAT signaling, shifting toward trans-signaling.","evidence":"Flow cytometry, STAT3/STAT1 phosphorylation and allele-specific expression in a genotyped cohort","pmids":["23593036"],"confidence":"High","gaps":["Cleavage enzyme not directly implicated here","Disease-level consequences inferred indirectly"]},{"year":2013,"claim":"Whether the variant alters circulating sIL-6R and disease was tested; carriers showed elevated serum sIL-6R linked to atopic dermatitis, connecting genotype to trans-signaling burden.","evidence":"Serum sIL-6R ELISA and GWAS meta-analysis across seven populations","pmids":["23582566"],"confidence":"Medium","gaps":["Causal mechanism for AD association not established","Mechanistic shedding step assayed in a separate study"]},{"year":2014,"claim":"How IL-6R drives oncogenic STAT3 was unresolved; a STAT3/miR-34a/IL-6R positive feedback loop was defined where STAT3 represses miR-34a, which targets IL-6R, driving EMT and metastasis.","evidence":"Luciferase reporters, STAT3 ChIP, miR-34a perturbation, CRC invasion assays, Mir34a-deficient mouse cancer model","pmids":["24642471"],"confidence":"High","gaps":["Loop generalization to non-CRC tumors not tested here","Quantitative loop dynamics not modeled"]},{"year":2015,"claim":"Whether the feedback loop extends to trans-signaling was open; miR-34a was shown to also target soluble IL-6R mRNA and lower secreted sIL-6R.","evidence":"Luciferase reporter of sIL-6R 3'UTR, conditioned-media ELISA, Western blot","pmids":["26091352"],"confidence":"Medium","gaps":["Same lab extension; independent replication absent","In vivo relevance of sIL-6R regulation not tested"]},{"year":2015,"claim":"The therapeutic potential of IL-6R blockade and its link to cancer stemness were unclear; ALDH-high cancer stem-like cells overexpressed CD126/gp130 and IL-6R/JAK1/STAT3 inhibition reduced the stem-like compartment.","evidence":"Flow cytometry, pharmacological pathway inhibition, organoid and xenograft assays","pmids":["26130650"],"confidence":"Medium","gaps":["Direct IL-6R dependence of stemness vs downstream effectors not isolated","Off-target inhibitor effects not excluded"]},{"year":2016,"claim":"The source of trans-signaling sIL-6R was debated; circulating sIL-6R was shown to enter inflamed tissue independently of local ADAM17 shedding.","evidence":"ADAM17 hypomorphic mice and air-pouch inflammation model","pmids":["27698010"],"confidence":"Medium","gaps":["Systemic shedding source not pinpointed","Model-specific; other inflammation contexts untested"]},{"year":2016,"claim":"Whether classical epithelial IL-6R signaling drives intestinal repair/cancer was tested; conditional IL-6R knockout showed classical signaling is dispensable for repair and carcinogenesis, with STAT3 responses restricted to cancer cells.","evidence":"Intestinal-epithelial IL-6R knockout mice, DSS and AOM-DSS models, organoid cultures","pmids":["27869785"],"confidence":"High","gaps":["Compensatory trans-signaling contribution not separately quantified","Cancer-cell STAT3 trigger not defined"]},{"year":2017,"claim":"Whether the Asp358Ala variant directly affects shedding was unproven; A358-containing peptides were more susceptible to ADAM10/ADAM17 cleavage, providing the molecular basis for elevated sIL-6R.","evidence":"In vitro cleavage assays with recombinant ADAM10/ADAM17 on peptide variants","pmids":["28106546"],"confidence":"Medium","gaps":["Peptide assay does not capture full-length receptor in membrane","Single method, single lab"]},{"year":2017,"claim":"Whether STAT3/miRNA loops drive chemoresistance was open; a STAT3/miR-204/IL-6R loop was shown to drive cisplatin resistance in ovarian cancer, reinforcing IL-6R as a feedback node.","evidence":"Luciferase reporter, STAT3 ChIP, miR-204 perturbation, in vitro/in vivo cisplatin assays","pmids":["28388577"],"confidence":"Medium","gaps":["Relative contribution of miR-204 vs miR-34a loops unclear","Clinical resistance correlation not established"]},{"year":2019,"claim":"How IL-6R abundance can be pharmacologically lowered was unknown; metformin reduced IL-6R via an AMPK/mTOR/miR-34a axis in myeloma, reducing IL-6 signaling.","evidence":"Western blot, qPCR, AMPK/mTOR modulators and miR-34a perturbation in myeloma lines","pmids":["30988378"],"confidence":"Medium","gaps":["Direct AMPK-to-miR-34a link not fully delineated","In vivo efficacy not addressed"]},{"year":2019,"claim":"How IL-6R hyperactivates STAT3 in myeloma was probed; high IL-6R confers IL-6 hypersensitivity and cooperates with ADAR1-P150 in a STAT3 feedforward loop.","evidence":"siRNA knockdown, co-IP, reporter assays and IL-6 stimulation in myeloma lines","pmids":["31413087"],"confidence":"Medium","gaps":["IL-6R-ADAR1 physical link is indirect (via STAT3)","Single-lab epistasis"]},{"year":2019,"claim":"Whether IL-6R cooperates with other receptors was unexplored; endothelial VEGFR2 signaling required co-signaling from IL-6R-gp130 and C3ar1/C5ar1 in a physical receptor complex.","evidence":"Co-IP, BRET, confocal imaging, receptor blockade and in vivo retinal angiogenesis","pmids":["30765465"],"confidence":"High","gaps":["Stoichiometry and assembly order of the receptor cluster unresolved","Generalizability beyond endothelium untested"]},{"year":2021,"claim":"Whether CD126 is a viable immunotherapy target was tested; CD126-directed CAR-T cells killed tumor cells antigen-specifically, with soluble CD126 binding potentially mitigating cytokine release syndrome.","evidence":"Flow cytometry, CAR-T killing assays, myeloma and prostate xenografts","pmids":["33414408"],"confidence":"Medium","gaps":["On-target normal-tissue toxicity not fully characterized","Clinical translation untested"]},{"year":2023,"claim":"Cell-type specificity of CNS IL-6 responsiveness was unclear; microglia-like cells expressing IL-6R responded with STAT3 activation while IL-6R-null neural progenitors did not, mapping responsiveness to receptor expression.","evidence":"hiPSC-derived microglia and NPC cultures, phospho-STAT3, RNAseq, flow cytometry","pmids":["36781081"],"confidence":"Medium","gaps":["Trans-signaling contribution in NPCs not tested","In vivo brain relevance not established"]},{"year":null,"claim":"The in vivo balance and tissue-specific switching between classical and trans-signaling, and the physiological regulators that determine receptor shedding versus surface retention, remain incompletely defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural/quantitative model linking shedding, sIL-6R, and sgp130 buffering in vivo","Tissue-specific protease control of shedding unresolved","Whether feedback loops operate uniformly across cancers unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,5,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,8,12]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,8,17]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,4,14]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,8,12]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,14,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,17,21]}],"complexes":["IL-6/IL-6R/gp130 signaling complex","sIL-6R:sgp130 binary complex"],"partners":["IL6","IL6ST","ADAM17","ADAM10","KDR","C3AR1","C5AR1","STAT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08887","full_name":"Interleukin-6 receptor subunit alpha","aliases":["IL-6R 1","Membrane glycoprotein 80","gp80"],"length_aa":468,"mass_kda":51.5,"function":"Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal (PubMed:28265003). Signal activation necessitate an association with IL6ST. Activation leads to the regulation of the immune response, acute-phase reactions and hematopoiesis (PubMed:30995492, PubMed:31235509). The interaction with membrane-bound IL6R and IL6ST stimulates 'classic signaling', the restricted expression of the IL6R limits classic IL6 signaling to only a few tissues such as the liver and some cells of the immune system. Whereas the binding of IL6 and soluble IL6R to IL6ST stimulates 'trans-signaling'. Alternatively, 'cluster signaling' occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells (Probable) Signaling via the membrane-bound IL6R is mostly regenerative and anti-inflammatory (Probable). Drives naive CD4(+) T cells to the Th17 lineage, through 'cluster signaling' by dendritic cells (By similarity) Soluble form of IL6 receptor (sIL6R) that acts as an agonist of IL6 activity (PubMed:21990364). The IL6:sIL6R complex (hyper-IL6) binds to IL6ST/gp130 on cell surfaces and induces signaling also on cells that do not express membrane-bound IL6R in a process called IL6 'trans-signaling'. sIL6R is causative for the pro-inflammatory properties of IL6 and an important player in the development of chronic inflammatory diseases (PubMed:21990364). In complex with IL6, is required for induction of VEGF production (PubMed:12794819). Plays a protective role during liver injury, being required for maintenance of tissue regeneration (By similarity). 'Trans-signaling' in central nervous system regulates energy and glucose homeostasis (By similarity) Soluble form of IL6 receptor (sIL6R) that acts as an agonist of IL6 activity (PubMed:21990364). The IL6:sIL6R complex (hyper-IL6) binds to IL6ST/gp130 on cell surfaces and induces signaling also on cells that do not express membrane-bound IL6R in a process called IL6 'trans-signaling'. sIL6R is causative for the pro-inflammatory properties of IL6 and an important player in the development of chronic inflammatory diseases (PubMed:21990364). In complex with IL6, is required for induction of VEGF production (PubMed:12794819). Plays a protective role during liver injury, being required for maintenance of tissue regeneration (By similarity). 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/27698010","citation_count":19,"is_preprint":false},{"pmid":"37461111","id":"PMC_37461111","title":"IL-1RA promotes oral squamous cell carcinoma malignancy through mitochondrial metabolism-mediated EGFR/JNK/SOX2 pathway.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37461111","citation_count":18,"is_preprint":false},{"pmid":"35216135","id":"PMC_35216135","title":"Classical Signaling and Trans-Signaling Pathways Stimulated by Megalobrama amblycephala IL-6 and IL-6R.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35216135","citation_count":18,"is_preprint":false},{"pmid":"30787661","id":"PMC_30787661","title":"Are IL1B, IL6 and IL6R Gene Variants Associated with Anterior Cruciate Ligament Rupture Susceptibility?","date":"2019","source":"Journal of sports science & 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difference in IL-1Ra gene polymorphism.","date":"2007","source":"Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research","url":"https://pubmed.ncbi.nlm.nih.gov/18052726","citation_count":17,"is_preprint":false},{"pmid":"26712690","id":"PMC_26712690","title":"CD126 and Targeted Therapy with Tocilizumab in Chronic Lymphocytic Leukemia.","date":"2015","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/26712690","citation_count":16,"is_preprint":false},{"pmid":"37256935","id":"PMC_37256935","title":"Constitutive IL-1RA production by modified immune cells protects against IL-1-mediated inflammatory disorders.","date":"2023","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37256935","citation_count":16,"is_preprint":false},{"pmid":"6409694","id":"PMC_6409694","title":"Loss and resynthesis of a developmentally regulated membrane protein (gp80) during dedifferentiation and redifferentiation in Dictyostelium.","date":"1983","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/6409694","citation_count":16,"is_preprint":false},{"pmid":"38242119","id":"PMC_38242119","title":"Inhibition of CSF-1R and IL-6R prevents conversion of cDC2s into immune incompetent tumor-induced DC3s boosting DC-driven therapy potential.","date":"2024","source":"Cell reports. Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38242119","citation_count":16,"is_preprint":false},{"pmid":"31328584","id":"PMC_31328584","title":"Interleukin-6 Receptor (IL-6R) Expression in Human Gastric Carcinoma and its Clinical Significance.","date":"2019","source":"Cancer investigation","url":"https://pubmed.ncbi.nlm.nih.gov/31328584","citation_count":16,"is_preprint":false},{"pmid":"39853717","id":"PMC_39853717","title":"Targeting p21-Positive Senescent Chondrocytes via IL-6R/JAK2 Inhibition to Alleviate Osteoarthritis.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/39853717","citation_count":15,"is_preprint":false},{"pmid":"32738192","id":"PMC_32738192","title":"CD4+CD126low/- Foxp3+ Cell Population Represents a Superior Subset of Regulatory T Cells in Treating Autoimmune Diseases.","date":"2020","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32738192","citation_count":15,"is_preprint":false},{"pmid":"21689450","id":"PMC_21689450","title":"Ten-color flow cytometry reveals distinct patterns of expression of CD124 and CD126 by developing thymocytes.","date":"2011","source":"BMC immunology","url":"https://pubmed.ncbi.nlm.nih.gov/21689450","citation_count":15,"is_preprint":false},{"pmid":"19010373","id":"PMC_19010373","title":"IL-6R distribution in normal human and cynomolgus monkey tissues.","date":"2008","source":"Regulatory toxicology and pharmacology : RTP","url":"https://pubmed.ncbi.nlm.nih.gov/19010373","citation_count":15,"is_preprint":false},{"pmid":"18008080","id":"PMC_18008080","title":"Impact of polymorphism in IL-1RA gene on the risk of cervical cancer.","date":"2008","source":"Archives of gynecology and obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/18008080","citation_count":15,"is_preprint":false},{"pmid":"39448992","id":"PMC_39448992","title":"Berberine-loaded PLGA nanoparticles alleviate ulcerative colitis by targeting IL-6/IL-6R axis.","date":"2024","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39448992","citation_count":14,"is_preprint":false},{"pmid":"31664694","id":"PMC_31664694","title":"Preparation and Evaluation of IL-1ra-Loaded Dextran/PLGA Microspheres for Inhibiting Periodontal Inflammation In Vitro.","date":"2020","source":"Inflammation","url":"https://pubmed.ncbi.nlm.nih.gov/31664694","citation_count":14,"is_preprint":false},{"pmid":"28972805","id":"PMC_28972805","title":"Role of IL-1ra and Granzyme B as biomarkers in active Crohn's disease patients.","date":"2017","source":"Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals","url":"https://pubmed.ncbi.nlm.nih.gov/28972805","citation_count":14,"is_preprint":false},{"pmid":"10460618","id":"PMC_10460618","title":"CD130 rather than CD126 expression is associated with disease activity in multiple myeloma.","date":"1999","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/10460618","citation_count":13,"is_preprint":false},{"pmid":"37243282","id":"PMC_37243282","title":"Association of Polymorphisms of IL-6 Pathway Genes (IL6, IL6R and IL6ST) with COVID-19 Severity in an Amazonian Population.","date":"2023","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/37243282","citation_count":12,"is_preprint":false},{"pmid":"10210772","id":"PMC_10210772","title":"Interleukin-6 receptor signaling. 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Elevated soluble IL-6R is also higher in atopic dermatitis patients versus controls, linking the variant to altered trans-signaling.\",\n      \"method\": \"ELISA measurement of serum sIL-6R; GWAS meta-analysis across 7 study populations with 7130 AD patients\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — large epidemiological validation with ELISA functional readout, single lab for mechanistic component\",\n      \"pmids\": [\"23582566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The IL6R p.D358A allele leads to increased proteolytic shedding of membrane-bound IL-6R; peptides containing A358 are more susceptible to cleavage by ADAM10 and ADAM17 compared to D358 peptides, providing a molecular mechanism for the genotype-dependent increase in circulating soluble IL-6R.\",\n      \"method\": \"In vitro cleavage assays with recombinant ADAM10 and ADAM17 on IL-6R peptide variants\",\n      \"journal\": \"Journal of Alzheimer's disease : JAD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay with mutagenesis, single lab, single method\",\n      \"pmids\": [\"28106546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In human osteoblasts, membrane-bound IL-6R (gp80) is nonfunctional and cannot activate gp130 signaling; only after shedding into soluble form (sIL-6R) via a protein kinase C-dependent mechanism does the IL-6/sIL-6R complex induce rapid tyrosine phosphorylation of gp130. PKC inhibitors block both spontaneous and PMA-induced IL-6R shedding and prevent gp130 activation.\",\n      \"method\": \"Immunoprecipitation, flow cytometry, tyrosine phosphorylation assays, neutralizing antibodies to sIL-6R and gp130, PKC inhibitors in osteoblast cell lines and primary osteoblasts\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with neutralizing antibodies and inhibitors, multiple osteoblast cell lines and primary cells, multiple orthogonal methods\",\n      \"pmids\": [\"11884403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Natural soluble IL-6R (sIL-6R, gp80) and natural soluble gp130 (sgp130) interact directly in the absence of IL-6 with a Kd of 2.8 nM as measured by surface plasmon resonance; this binary complex is unable to bind IL-6, suggesting that circulating sgp130 can inhibit IL-6 trans-signaling by sequestering sIL-6R.\",\n      \"method\": \"Surface plasmon resonance (Biacore) using proteins purified from human plasma\",\n      \"journal\": \"European cytokine network\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro binding kinetics with purified natural proteins, single lab, single method\",\n      \"pmids\": [\"10210772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human herpesvirus 8 vIL-6 can signal through gp130 in the absence of gp80 (IL-6R alpha); chimeric and point-mutant analysis showed that the B helix of vIL-6 is absolutely required for gp80-independent signaling, and gp80 was found to stabilize vIL-6-induced gp130:gp130 signaling complexes even when not required for signaling initiation.\",\n      \"method\": \"Site-directed mutagenesis, chimeric IL-6 constructs, co-immunoprecipitation, signaling assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with functional reconstitution and co-IP, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"16973585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IL-6 activates STAT3, which directly represses the MIR34A gene via a conserved STAT3-binding site. miR-34a in turn directly targets IL-6R mRNA (both membrane-bound form). This creates an IL-6R/STAT3/miR-34a positive feedback loop that is required for IL-6-induced EMT, invasion, and metastasis in colorectal cancer cells. p53 activation disrupts this loop via miR-34a-dependent IL-6R downregulation.\",\n      \"method\": \"Luciferase reporter assays, miR-34a gain/loss of function, STAT3 ChIP, CRC cell invasion assays, Mir34a-deficient mouse model of colitis-associated cancer\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter assays, genetic mouse model, human tumor data), replicated across multiple cancer cell lines\",\n      \"pmids\": [\"24642471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"miR-34a directly targets and represses both the membrane-bound IL-6R mRNA and the mRNA encoding soluble IL-6R (sIL-6R); ectopic miR-34a expression reduced sIL-6R protein concentration in conditioned media of CRC cell lines, extending the IL-6R/STAT3/miR-34a feedback loop to include trans-signaling.\",\n      \"method\": \"Luciferase reporter assay for sIL-6R 3'UTR targeting, ELISA of conditioned media, Western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR validation plus protein level readout, same lab as PMID 24642471 but adds sIL-6R as new target\",\n      \"pmids\": [\"26091352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CD4+CD25- T cells express both CD126 (IL-6R alpha) and CD130 (gp130) and show STAT3 phosphorylation after IL-6 or hyper-IL-6 stimulation, whereas CD4+CD25high Treg cells express CD126 but little CD130 and show markedly less STAT3 phosphorylation; downmodulation of CD126 and CD130 after ligand binding occurred on conventional T cells but not Tregs. MAPK ERK1/2 was not activated by CD130 dimerization.\",\n      \"method\": \"Flow cytometry, phospho-STAT3 and phospho-ERK1/2 intracellular staining, surface receptor modulation assays\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct functional signaling readout tied to receptor expression across defined T cell subsets, multiple methods, single lab\",\n      \"pmids\": [\"16540526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Oncostatin M (OSM) upregulates IL-6R (gp80) mRNA approximately 2-fold in rat hepatoma cells, an effect additive with dexamethasone, whereas IL-1 inhibits dexamethasone-mediated IL-6R mRNA induction and induces a smaller IL-6R transcript lacking transmembrane and cytoplasmic domains, suggesting alternate splicing to generate a soluble form. gp130 expression was not substantially regulated under the same conditions.\",\n      \"method\": \"Northern blot / steady-state mRNA analysis of cytokine-stimulated H-35 rat hepatoma cells\",\n      \"journal\": \"Cytokine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple cytokine conditions with transcript-level analysis; two independent observations (OSM induction and IL-1-induced splice variant), single lab\",\n      \"pmids\": [\"8580365\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In multiple myeloma cells, metformin specifically decreases IL-6R expression via AMPK, mTOR, and miR-34a pathways, thereby reducing IL-6 signaling.\",\n      \"method\": \"Western blot, qPCR, AMPK/mTOR pathway inhibitors and activators, miR-34a modulation in myeloma cell lines\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway inhibitors and molecular readouts in a single-lab study establish the AMPK/mTOR/miR-34a axis controlling IL-6R expression\",\n      \"pmids\": [\"30988378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"IL-6R (CD126) and ADAR1-P150 cooperate to hyperactivate the STAT3 pathway in multiple myeloma. High IL-6R expression confers hypersensitivity to IL-6 binding, while ADAR1-P150 is a direct STAT3 transcriptional target that in turn physically interacts with and stabilizes STAT3, forming a feedforward loop. Concomitant knockdown of both IL-6R and ADAR1 impeded IL-6-induced STAT3 pathway activation more than either alone.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation, transcriptional reporter assays, IL-6 stimulation assays in myeloma cell lines\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus double knockdown epistasis and IL-6 stimulation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"31413087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"VEGFR2 auto-phosphorylation and downstream Src, ERK, AKT, mTOR, and STAT3 activation in endothelial cells requires concurrent IL-6R-gp130 and C3ar1/C5ar1 co-signaling; blockade of either IL-6R or C3ar1/C5ar1 completely abolished VEGFR2 signaling and EC cell cycle entry. Co-immunoprecipitation and BRET assays demonstrated physical interaction among VEGFR2, IL-6R-gp130, and C3ar1/C5ar1.\",\n      \"method\": \"Co-immunoprecipitation, BRET assay, confocal microscopy, ligand pulldown, receptor blockade, in vivo retinal angiogenesis model\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal interaction assays (Co-IP, BRET, pulldown) plus functional rescue in vitro and in vivo, single rigorous study\",\n      \"pmids\": [\"30765465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In intestinal epithelial cells, classical IL-6 signaling through membrane-bound IL-6R (IL-6RΔIEC knockout mice) is dispensable for intestinal repair and does not protect against DSS-induced colitis or inflammation-induced carcinogenesis, while primary non-malignant intestinal organoids do not respond to IL-6 classic signaling; IL-6 STAT3 activation was only observed in colonic cancer cell lines.\",\n      \"method\": \"Intestinal epithelial-specific IL-6R knockout mice (IL-6RΔIEC), DSS colitis model, azoxymethane-DSS carcinogenesis model, intestinal organoid culture, STAT3 phosphorylation assay\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO with two independent in vivo disease models and organoid validation; negative finding that classic IL-6R signaling is dispensable for epithelial repair\",\n      \"pmids\": [\"27869785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Circulating soluble IL-6R (sIL-6R) enters inflamed tissue from the circulation in an ADAM17-independent manner to enable IL-6 trans-signaling and mononuclear cell recruitment; using ADAM17 hypomorphic mice with ~5% normal ADAM17 levels, local ADAM17-mediated shedding within the air pouch was shown not to be the source of sIL-6R driving trans-signaling in this model.\",\n      \"method\": \"ADAM17 hypomorphic mouse model, murine air pouch inflammation model, cytokine and cell infiltration measurements\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic hypomorph model with defined cellular readout; single lab but rigorous genetic approach\",\n      \"pmids\": [\"27698010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A peptide (S7) identified by phage display library screening specifically binds to the IL-6R alpha chain (gp80) and blocks IL-6 binding to IL-6R alpha in a dose-dependent manner, inhibits IL-6-mediated survival signaling, VEGF-A expression, and angiogenesis in cancer cells in vitro, and suppresses IL-6-induced cervical tumor growth in vivo.\",\n      \"method\": \"Phage display, competitive binding assay, cell signaling assays, VEGF-A ELISA, SCID mouse xenograft\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding competition assay plus functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"15930303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Epitope mapping of human IL-6R (gp80) using 7 monoclonal antibodies identified four distinct epitopes; two epitopes (recognized by M37, M113, M139, M164 group and M195) are involved in IL-6 binding and antibodies against them inhibit IL-6 binding and IL-6-dependent cell proliferation, while two other epitopes (M91, M182) do not participate in IL-6 binding, though M182 still interferes with the proliferative response.\",\n      \"method\": \"ELISA, FACS, Western blot, cross-blocking assays, Biacore surface plasmon resonance, IL-6-dependent cell proliferation assay\",\n      \"journal\": \"European cytokine network\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal epitope mapping methods including SPR, single lab\",\n      \"pmids\": [\"7524715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD126 (IL-6R alpha chain) is expressed on neoplastic plasma cells from ~90% of myeloma patients and MGUS but is undetectable on normal plasma cells; expression is highest on VLA-5- immature myeloma cells and is not induced by bone marrow stromal cells, as neoplastic cells show higher CD126 levels than normal plasma cells from the same marrow.\",\n      \"method\": \"4-color flow cytometry of bone marrow samples from 93 myeloma, 66 MGUS/plasmacytoma, and 11 normal subjects\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct flow cytometry with large patient cohort and internal controls from same marrow, single lab\",\n      \"pmids\": [\"11090073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Serum soluble IL-6R (sIL-6R) levels increased three-fold during HgCl2-induced acute kidney injury in mice; stimulation with an IL-6/sIL-6R fusion protein activated STAT3 in renal tubular epithelium (which lacks membrane IL-6R) and prevented AKI, suggesting IL-6 trans-signaling through sIL-6R is protective in kidney injury and mediates its effect partly through reduction of lipid peroxidation.\",\n      \"method\": \"IL-6-deficient mouse model, neutrophil depletion, IL-6/sIL-6R fusion protein administration, STAT3 immunohistochemistry, lipid peroxidation assay\",\n      \"journal\": \"Journal of the American Society of Nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout and pharmacological reconstitution with functional cellular readout, single lab\",\n      \"pmids\": [\"18337485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Human forebrain neural progenitor cells (NPCs) did not respond to IL-6 stimulation due to absence of IL-6R expression and no soluble IL-6Ra secretion, whereas hiPSC-derived microglia-like cells expressing canonical IL-6Ra showed STAT3 phosphorylation, upregulation of IL6, JMJD3 and IL10, and increased motility upon acute IL-6 exposure.\",\n      \"method\": \"hiPSC-derived microglia and NPC cultures, STAT3 phosphorylation assay, bulk RNAseq, cytokine multiplex, flow cytometry for IL-6R expression\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in defined human cell models, single lab; cell-type specificity of IL-6R signaling directly established\",\n      \"pmids\": [\"36781081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CD4+Foxp3+ Treg cells with low/negative CD126 (IL-6R alpha) expression are functionally superior and more stable than CD126Hi Treg cells, even in the presence of IL-6 and inflammation; CD126Lo/- Tregs successfully treated colitis and collagen-induced arthritis in mice, whereas CD126Hi Tregs failed. CD126 expression on Treg cells positively correlated with RA severity.\",\n      \"method\": \"In vitro stability assays with IL-6, adoptive transfer in colitis and CIA mouse models, flow cytometry\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo functional data with defined cell subsets, multiple disease models, single lab\",\n      \"pmids\": [\"32738192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ALDH-high cancer stem-like cells in endometrial cancer show upregulated IL-6R subunits CD126 and GP130; targeted inhibition of IL-6R and its downstream effectors JAK1 and STAT3 dramatically reduced tumor cell growth and diminished the ALDHhi/CD126+ stem-like component.\",\n      \"method\": \"Flow cytometry for ALDH activity and CD126/GP130 expression, pharmacological IL-6R/JAK1/STAT3 inhibition, organoid and xenograft assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — expression analysis linked to functional inhibition with in vivo validation, single lab\",\n      \"pmids\": [\"26130650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IL-6 activates STAT3, which directly represses miR-204 via a conserved STAT3-binding site; loss of miR-204 derepresses IL-6R expression, forming an IL-6R/STAT3/miR-204 positive feedback loop that drives cisplatin resistance in epithelial ovarian cancer cells; exogenous miR-204 blocked this circuit and enhanced cisplatin sensitivity in vitro and in vivo.\",\n      \"method\": \"Luciferase reporter, STAT3 ChIP, miR-204 gain/loss of function, in vitro and in vivo cisplatin sensitivity assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus in vivo validation, single lab; analogous loop to CRC miR-34a finding but independent study\",\n      \"pmids\": [\"28388577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CD126 (IL-6R) is broadly expressed on multiple hematologic and solid tumor types; CAR-T cells targeting CD126 kill tumor cells in an antigen-specific manner proportional to CD126 expression levels; soluble CD126 does not interfere with CAR-T cell killing; and binding of sIL-6R by CD126 CAR-T cells may mitigate cytokine release syndrome (evidenced by lower murine SAA-3 levels).\",\n      \"method\": \"Flow cytometry for CD126 expression, CAR-T killing assays, myeloma and prostate xenograft mouse models\",\n      \"journal\": \"Blood cancer journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — antigen-specific killing validated in vitro and in two xenograft models, single lab\",\n      \"pmids\": [\"33414408\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IL-6R (CD126/gp80) is the ligand-binding alpha-chain of the IL-6 receptor complex that, upon IL-6 binding, recruits the signal-transducing subunit gp130 to activate JAK/STAT3 and MAPK signaling; membrane-bound IL-6R mediates classical signaling in cells expressing both subunits, while proteolytic shedding of IL-6R by ADAM10/ADAM17 (facilitated by the disease-associated Asp358Ala variant) generates soluble IL-6R (sIL-6R) that enables IL-6 trans-signaling in cells lacking membrane IL-6R, with sgp130 able to sequester sIL-6R to dampen trans-signaling; IL-6R expression and signaling are regulated by miRNAs (including miR-34a, miR-204), cytokines (OSM, IL-1), and AMPK/mTOR, and IL-6R participates in oncogenic feedback loops (IL-6R/STAT3/miR-34a) that promote EMT, invasion, and drug resistance in multiple cancers.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IL6R encodes the ligand-binding alpha-chain (gp80/CD126) of the interleukin-6 receptor, whose engagement of IL-6 governs activation of the signal-transducing subunit gp130 and downstream STAT3 phosphorylation across immune, epithelial, and tumor cells [#3, #8]. Receptor function is partitioned between membrane-bound classical signaling and trans-signaling driven by a soluble IL-6R ectodomain (sIL-6R) generated by proteolytic shedding through ADAM10 and ADAM17; the IL-6/sIL-6R complex activates gp130 in cells lacking membrane IL-6R, while soluble gp130 directly binds sIL-6R (Kd ~2.8 nM) to sequester it and dampen trans-signaling [#2, #4]. In some cell types membrane IL-6R alone is insufficient: in osteoblasts only the shed soluble form, released by a PKC-dependent mechanism, activates gp130, and classical IL-6R signaling is dispensable for intestinal epithelial repair and inflammation-driven carcinogenesis [#3, #13]. The common Asp358Ala (rs2228145) variant shifts this balance by increasing soluble-isoform transcription and enhancing ADAM10/ADAM17 cleavage of the receptor, lowering surface IL-6R and raising circulating sIL-6R [#0, #1, #2]. IL-6R sits in oncogenic STAT3 feedback circuits in which STAT3 represses miR-34a and miR-204, both of which directly target IL-6R mRNA, creating positive feedback loops that promote EMT, invasion, drug resistance, and cancer stemness [#6, #22, #21]. Receptor abundance is further controlled by an AMPK/mTOR/miR-34a axis, and CD126 is selectively overexpressed on malignant plasma cells, making it both a signaling determinant and a therapeutic target via blocking peptides and CAR-T cells [#10, #17, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Defining which surfaces of IL-6R mediate ligand binding was needed to map the functional receptor architecture; epitope mapping resolved distinct ligand-binding versus non-binding regions of gp80.\",\n      \"evidence\": \"Monoclonal antibody epitope mapping with ELISA, FACS, cross-blocking, SPR and proliferation assays\",\n      \"pmids\": [\"7524715\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No atomic structure of the IL-6/IL-6R/gp130 complex established here\", \"Did not address gp130 recruitment geometry\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"It was unknown how IL-6R expression is transcriptionally regulated by other cytokines; OSM and IL-1 were shown to modulate IL-6R mRNA and generate a transmembrane-lacking transcript, hinting at a soluble form via splicing.\",\n      \"evidence\": \"Northern blot mRNA analysis of cytokine-stimulated rat hepatoma cells\",\n      \"pmids\": [\"8580365\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Splice variant inferred from transcript size, not sequenced\", \"Protein-level confirmation of soluble form absent\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"How soluble gp130 might restrain trans-signaling was unclear; direct binding measurements showed sgp130 binds sIL-6R in the absence of IL-6, establishing a sequestration mechanism.\",\n      \"evidence\": \"Surface plasmon resonance with proteins purified from human plasma\",\n      \"pmids\": [\"10210772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single in vitro binding method\", \"Physiological buffering capacity in vivo not quantified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Whether membrane IL-6R is universally functional was untested; in osteoblasts membrane gp80 was nonfunctional and only PKC-dependent shedding to sIL-6R enabled gp130 activation.\",\n      \"evidence\": \"Immunoprecipitation, neutralizing antibodies, PKC inhibitors in osteoblast lines and primary cells\",\n      \"pmids\": [\"11884403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PKC-targeted protease not identified\", \"Generalizability beyond osteoblasts not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The roles of gp80 in gp130 signaling complexes were probed using viral IL-6; vIL-6 signals through gp130 without gp80, yet gp80 stabilizes the gp130 signaling complex, clarifying gp80's structural contribution.\",\n      \"evidence\": \"Site-directed mutagenesis, chimeric constructs, co-IP and signaling assays\",\n      \"pmids\": [\"16973585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relevance of vIL-6 mechanism to human IL-6 signaling limited\", \"Stoichiometry of stabilized complex not resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Cell-type-specific IL-6 responsiveness was unexplained; differential CD126/CD130 expression across T-cell subsets dictated STAT3 activation, with Tregs poorly responsive due to low gp130.\",\n      \"evidence\": \"Flow cytometry and phospho-STAT3/ERK staining across T-cell subsets\",\n      \"pmids\": [\"16540526\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of Treg-specific receptor regulation not defined\", \"Functional consequence in vivo not tested here\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Whether trans-signaling is purely pathogenic was open; in kidney injury IL-6/sIL-6R trans-signaling activated STAT3 in tubular epithelium lacking membrane IL-6R and was protective.\",\n      \"evidence\": \"IL-6-deficient mice, IL-6/sIL-6R fusion protein, STAT3 IHC, lipid peroxidation assays\",\n      \"pmids\": [\"18337485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct source of endogenous sIL-6R not defined\", \"Protective mechanism beyond lipid peroxidation incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The functional consequence of the Asp358Ala variant was unknown; it was shown to favor soluble isoform transcription, reduce surface IL-6R, and impair classical STAT signaling, shifting toward trans-signaling.\",\n      \"evidence\": \"Flow cytometry, STAT3/STAT1 phosphorylation and allele-specific expression in a genotyped cohort\",\n      \"pmids\": [\"23593036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cleavage enzyme not directly implicated here\", \"Disease-level consequences inferred indirectly\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Whether the variant alters circulating sIL-6R and disease was tested; carriers showed elevated serum sIL-6R linked to atopic dermatitis, connecting genotype to trans-signaling burden.\",\n      \"evidence\": \"Serum sIL-6R ELISA and GWAS meta-analysis across seven populations\",\n      \"pmids\": [\"23582566\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal mechanism for AD association not established\", \"Mechanistic shedding step assayed in a separate study\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"How IL-6R drives oncogenic STAT3 was unresolved; a STAT3/miR-34a/IL-6R positive feedback loop was defined where STAT3 represses miR-34a, which targets IL-6R, driving EMT and metastasis.\",\n      \"evidence\": \"Luciferase reporters, STAT3 ChIP, miR-34a perturbation, CRC invasion assays, Mir34a-deficient mouse cancer model\",\n      \"pmids\": [\"24642471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Loop generalization to non-CRC tumors not tested here\", \"Quantitative loop dynamics not modeled\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Whether the feedback loop extends to trans-signaling was open; miR-34a was shown to also target soluble IL-6R mRNA and lower secreted sIL-6R.\",\n      \"evidence\": \"Luciferase reporter of sIL-6R 3'UTR, conditioned-media ELISA, Western blot\",\n      \"pmids\": [\"26091352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Same lab extension; independent replication absent\", \"In vivo relevance of sIL-6R regulation not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The therapeutic potential of IL-6R blockade and its link to cancer stemness were unclear; ALDH-high cancer stem-like cells overexpressed CD126/gp130 and IL-6R/JAK1/STAT3 inhibition reduced the stem-like compartment.\",\n      \"evidence\": \"Flow cytometry, pharmacological pathway inhibition, organoid and xenograft assays\",\n      \"pmids\": [\"26130650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct IL-6R dependence of stemness vs downstream effectors not isolated\", \"Off-target inhibitor effects not excluded\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The source of trans-signaling sIL-6R was debated; circulating sIL-6R was shown to enter inflamed tissue independently of local ADAM17 shedding.\",\n      \"evidence\": \"ADAM17 hypomorphic mice and air-pouch inflammation model\",\n      \"pmids\": [\"27698010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Systemic shedding source not pinpointed\", \"Model-specific; other inflammation contexts untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Whether classical epithelial IL-6R signaling drives intestinal repair/cancer was tested; conditional IL-6R knockout showed classical signaling is dispensable for repair and carcinogenesis, with STAT3 responses restricted to cancer cells.\",\n      \"evidence\": \"Intestinal-epithelial IL-6R knockout mice, DSS and AOM-DSS models, organoid cultures\",\n      \"pmids\": [\"27869785\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensatory trans-signaling contribution not separately quantified\", \"Cancer-cell STAT3 trigger not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether the Asp358Ala variant directly affects shedding was unproven; A358-containing peptides were more susceptible to ADAM10/ADAM17 cleavage, providing the molecular basis for elevated sIL-6R.\",\n      \"evidence\": \"In vitro cleavage assays with recombinant ADAM10/ADAM17 on peptide variants\",\n      \"pmids\": [\"28106546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptide assay does not capture full-length receptor in membrane\", \"Single method, single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether STAT3/miRNA loops drive chemoresistance was open; a STAT3/miR-204/IL-6R loop was shown to drive cisplatin resistance in ovarian cancer, reinforcing IL-6R as a feedback node.\",\n      \"evidence\": \"Luciferase reporter, STAT3 ChIP, miR-204 perturbation, in vitro/in vivo cisplatin assays\",\n      \"pmids\": [\"28388577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of miR-204 vs miR-34a loops unclear\", \"Clinical resistance correlation not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"How IL-6R abundance can be pharmacologically lowered was unknown; metformin reduced IL-6R via an AMPK/mTOR/miR-34a axis in myeloma, reducing IL-6 signaling.\",\n      \"evidence\": \"Western blot, qPCR, AMPK/mTOR modulators and miR-34a perturbation in myeloma lines\",\n      \"pmids\": [\"30988378\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct AMPK-to-miR-34a link not fully delineated\", \"In vivo efficacy not addressed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"How IL-6R hyperactivates STAT3 in myeloma was probed; high IL-6R confers IL-6 hypersensitivity and cooperates with ADAR1-P150 in a STAT3 feedforward loop.\",\n      \"evidence\": \"siRNA knockdown, co-IP, reporter assays and IL-6 stimulation in myeloma lines\",\n      \"pmids\": [\"31413087\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IL-6R-ADAR1 physical link is indirect (via STAT3)\", \"Single-lab epistasis\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether IL-6R cooperates with other receptors was unexplored; endothelial VEGFR2 signaling required co-signaling from IL-6R-gp130 and C3ar1/C5ar1 in a physical receptor complex.\",\n      \"evidence\": \"Co-IP, BRET, confocal imaging, receptor blockade and in vivo retinal angiogenesis\",\n      \"pmids\": [\"30765465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the receptor cluster unresolved\", \"Generalizability beyond endothelium untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Whether CD126 is a viable immunotherapy target was tested; CD126-directed CAR-T cells killed tumor cells antigen-specifically, with soluble CD126 binding potentially mitigating cytokine release syndrome.\",\n      \"evidence\": \"Flow cytometry, CAR-T killing assays, myeloma and prostate xenografts\",\n      \"pmids\": [\"33414408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"On-target normal-tissue toxicity not fully characterized\", \"Clinical translation untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cell-type specificity of CNS IL-6 responsiveness was unclear; microglia-like cells expressing IL-6R responded with STAT3 activation while IL-6R-null neural progenitors did not, mapping responsiveness to receptor expression.\",\n      \"evidence\": \"hiPSC-derived microglia and NPC cultures, phospho-STAT3, RNAseq, flow cytometry\",\n      \"pmids\": [\"36781081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trans-signaling contribution in NPCs not tested\", \"In vivo brain relevance not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The in vivo balance and tissue-specific switching between classical and trans-signaling, and the physiological regulators that determine receptor shedding versus surface retention, remain incompletely defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural/quantitative model linking shedding, sIL-6R, and sgp130 buffering in vivo\", \"Tissue-specific protease control of shedding unresolved\", \"Whether feedback loops operate uniformly across cancers unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 5, 16]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 8, 12]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 8, 17]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 4, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 8, 12]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 14, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 17, 21]}\n    ],\n    \"complexes\": [\"IL-6/IL-6R/gp130 signaling complex\", \"sIL-6R:sgp130 binary complex\"],\n    \"partners\": [\"IL6\", \"IL6ST\", \"ADAM17\", \"ADAM10\", \"KDR\", \"C3AR1\", \"C5AR1\", \"STAT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}