Affinage

IL6R

Interleukin-6 receptor subunit alpha · UniProt P08887

Length
468 aa
Mass
51.5 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1994 Medium

    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

    PMID:7524715

    Open questions at the time
    • No atomic structure of the IL-6/IL-6R/gp130 complex established here
    • Did not address gp130 recruitment geometry
  2. 1995 Medium

    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

    PMID:8580365

    Open questions at the time
    • Splice variant inferred from transcript size, not sequenced
    • Protein-level confirmation of soluble form absent
  3. 1999 Medium

    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

    PMID:10210772

    Open questions at the time
    • Single in vitro binding method
    • Physiological buffering capacity in vivo not quantified
  4. 2002 High

    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

    PMID:11884403

    Open questions at the time
    • PKC-targeted protease not identified
    • Generalizability beyond osteoblasts not addressed
  5. 2006 High

    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

    PMID:16973585

    Open questions at the time
    • Relevance of vIL-6 mechanism to human IL-6 signaling limited
    • Stoichiometry of stabilized complex not resolved
  6. 2006 Medium

    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

    PMID:16540526

    Open questions at the time
    • Mechanism of Treg-specific receptor regulation not defined
    • Functional consequence in vivo not tested here
  7. 2008 Medium

    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

    PMID:18337485

    Open questions at the time
    • Direct source of endogenous sIL-6R not defined
    • Protective mechanism beyond lipid peroxidation incomplete
  8. 2013 High

    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

    PMID:23593036

    Open questions at the time
    • Cleavage enzyme not directly implicated here
    • Disease-level consequences inferred indirectly
  9. 2013 Medium

    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

    PMID:23582566

    Open questions at the time
    • Causal mechanism for AD association not established
    • Mechanistic shedding step assayed in a separate study
  10. 2014 High

    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

    PMID:24642471

    Open questions at the time
    • Loop generalization to non-CRC tumors not tested here
    • Quantitative loop dynamics not modeled
  11. 2015 Medium

    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

    PMID:26091352

    Open questions at the time
    • Same lab extension; independent replication absent
    • In vivo relevance of sIL-6R regulation not tested
  12. 2015 Medium

    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

    PMID:26130650

    Open questions at the time
    • Direct IL-6R dependence of stemness vs downstream effectors not isolated
    • Off-target inhibitor effects not excluded
  13. 2016 Medium

    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

    PMID:27698010

    Open questions at the time
    • Systemic shedding source not pinpointed
    • Model-specific; other inflammation contexts untested
  14. 2016 High

    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

    PMID:27869785

    Open questions at the time
    • Compensatory trans-signaling contribution not separately quantified
    • Cancer-cell STAT3 trigger not defined
  15. 2017 Medium

    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

    PMID:28106546

    Open questions at the time
    • Peptide assay does not capture full-length receptor in membrane
    • Single method, single lab
  16. 2017 Medium

    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

    PMID:28388577

    Open questions at the time
    • Relative contribution of miR-204 vs miR-34a loops unclear
    • Clinical resistance correlation not established
  17. 2019 Medium

    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

    PMID:30988378

    Open questions at the time
    • Direct AMPK-to-miR-34a link not fully delineated
    • In vivo efficacy not addressed
  18. 2019 Medium

    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

    PMID:31413087

    Open questions at the time
    • IL-6R-ADAR1 physical link is indirect (via STAT3)
    • Single-lab epistasis
  19. 2019 High

    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

    PMID:30765465

    Open questions at the time
    • Stoichiometry and assembly order of the receptor cluster unresolved
    • Generalizability beyond endothelium untested
  20. 2021 Medium

    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

    PMID:33414408

    Open questions at the time
    • On-target normal-tissue toxicity not fully characterized
    • Clinical translation untested
  21. 2023 Medium

    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

    PMID:36781081

    Open questions at the time
    • Trans-signaling contribution in NPCs not tested
    • In vivo brain relevance not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 3 GO:0098772 molecular function regulator activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3
Partners
ADAM10ADAM17C3AR1C5AR1IL6IL6STKDRSTAT3
Complex memberships
IL-6/IL-6R/gp130 signaling complexsIL-6R:sgp130 binary complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 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. Flow cytometry of PBMCs from 128 volunteers, STAT3/STAT1 phosphorylation assays, allele-specific expression analysis PLoS genetics High 23593036
2013 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. ELISA measurement of serum sIL-6R; GWAS meta-analysis across 7 study populations with 7130 AD patients The Journal of allergy and clinical immunology Medium 23582566
2017 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. In vitro cleavage assays with recombinant ADAM10 and ADAM17 on IL-6R peptide variants Journal of Alzheimer's disease : JAD Medium 28106546
2002 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. Immunoprecipitation, flow cytometry, tyrosine phosphorylation assays, neutralizing antibodies to sIL-6R and gp130, PKC inhibitors in osteoblast cell lines and primary osteoblasts The Journal of biological chemistry High 11884403
1999 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. Surface plasmon resonance (Biacore) using proteins purified from human plasma European cytokine network Medium 10210772
2006 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. Site-directed mutagenesis, chimeric IL-6 constructs, co-immunoprecipitation, signaling assays Journal of virology High 16973585
2014 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. Luciferase reporter assays, miR-34a gain/loss of function, STAT3 ChIP, CRC cell invasion assays, Mir34a-deficient mouse model of colitis-associated cancer The Journal of clinical investigation High 24642471
2015 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. Luciferase reporter assay for sIL-6R 3'UTR targeting, ELISA of conditioned media, Western blot Oncotarget Medium 26091352
2006 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. Flow cytometry, phospho-STAT3 and phospho-ERK1/2 intracellular staining, surface receptor modulation assays International immunology Medium 16540526
1995 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. Northern blot / steady-state mRNA analysis of cytokine-stimulated H-35 rat hepatoma cells Cytokine Medium 8580365
2019 In multiple myeloma cells, metformin specifically decreases IL-6R expression via AMPK, mTOR, and miR-34a pathways, thereby reducing IL-6 signaling. Western blot, qPCR, AMPK/mTOR pathway inhibitors and activators, miR-34a modulation in myeloma cell lines Leukemia Medium 30988378
2019 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. siRNA knockdown, co-immunoprecipitation, transcriptional reporter assays, IL-6 stimulation assays in myeloma cell lines Haematologica Medium 31413087
2019 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. Co-immunoprecipitation, BRET assay, confocal microscopy, ligand pulldown, receptor blockade, in vivo retinal angiogenesis model Journal of cell science High 30765465
2016 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. Intestinal epithelial-specific IL-6R knockout mice (IL-6RΔIEC), DSS colitis model, azoxymethane-DSS carcinogenesis model, intestinal organoid culture, STAT3 phosphorylation assay Oncogenesis High 27869785
2016 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. ADAM17 hypomorphic mouse model, murine air pouch inflammation model, cytokine and cell infiltration measurements Journal of immunology Medium 27698010
2005 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. Phage display, competitive binding assay, cell signaling assays, VEGF-A ELISA, SCID mouse xenograft Cancer research Medium 15930303
1994 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. ELISA, FACS, Western blot, cross-blocking assays, Biacore surface plasmon resonance, IL-6-dependent cell proliferation assay European cytokine network Medium 7524715
2000 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. 4-color flow cytometry of bone marrow samples from 93 myeloma, 66 MGUS/plasmacytoma, and 11 normal subjects Blood Medium 11090073
2008 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. IL-6-deficient mouse model, neutrophil depletion, IL-6/sIL-6R fusion protein administration, STAT3 immunohistochemistry, lipid peroxidation assay Journal of the American Society of Nephrology Medium 18337485
2023 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. hiPSC-derived microglia and NPC cultures, STAT3 phosphorylation assay, bulk RNAseq, cytokine multiplex, flow cytometry for IL-6R expression Brain, behavior, and immunity Medium 36781081
2020 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. In vitro stability assays with IL-6, adoptive transfer in colitis and CIA mouse models, flow cytometry Molecular therapy Medium 32738192
2015 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. Flow cytometry for ALDH activity and CD126/GP130 expression, pharmacological IL-6R/JAK1/STAT3 inhibition, organoid and xenograft assays Cancer research Medium 26130650
2017 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. Luciferase reporter, STAT3 ChIP, miR-204 gain/loss of function, in vitro and in vivo cisplatin sensitivity assays Oncotarget Medium 28388577
2021 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). Flow cytometry for CD126 expression, CAR-T killing assays, myeloma and prostate xenograft mouse models Blood cancer journal Medium 33414408

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. American journal of physiology. Endocrinology and metabolism 814 12857678
2014 IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. The Journal of clinical investigation 637 24642471
2002 The balance between IL-1 and IL-1Ra in disease. Cytokine & growth factor reviews 579 12220547
2022 IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines. Nature immunology 406 35332327
2008 IL-6/IL-6R axis plays a critical role in acute kidney injury. Journal of the American Society of Nephrology : JASN 315 18337485
2011 Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet (London, England) 302 21907864
1997 Interleukin 1 receptor antagonist (IL-1Ra) is an acute-phase protein. The Journal of clinical investigation 256 9185517
2013 Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLoS genetics 246 23593036
1994 Expression of multiple cytokines and IL-1RA in the uvea and retina during endotoxin-induced uveitis in the rat. Investigative ophthalmology & visual science 167 7928184
2006 The role of IL-1 and IL-1Ra in joint inflammation and cartilage degradation. Vitamins and hormones 138 17027524
2023 Therapeutic potential of IL6R blockade for the treatment of sepsis and sepsis-related death: A Mendelian randomisation study. PLoS medicine 100 36716318
2016 Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer. Oncotarget 95 26840088
2006 Differential expression of CD126 and CD130 mediates different STAT-3 phosphorylation in CD4+CD25- and CD25high regulatory T cells. International immunology 90 16540526
2013 A functional IL-6 receptor (IL6R) variant is a risk factor for persistent atopic dermatitis. The Journal of allergy and clinical immunology 85 23582566
2020 Targeting miR-10a-5p/IL-6R axis for reducing IL-6-induced cartilage cell ferroptosis. Experimental and molecular pathology 76 33166496
2016 Cell therapy centered on IL-1Ra is neuroprotective in experimental stroke. Acta neuropathologica 72 26860727
2015 IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden. Cancer research 71 26130650
2005 A novel peptide specifically binding to interleukin-6 receptor (gp80) inhibits angiogenesis and tumor growth. Cancer research 71 15930303
2009 IL-1/IL-1ra balance in the brain revisited - evidence from transgenic mouse models. Brain, behavior, and immunity 65 19258032
2015 Diacerein-mediated inhibition of IL-6/IL-6R signaling induces apoptotic effects on breast cancer. Oncogene 63 26616855
2000 The interleukin-6 receptor alpha-chain (CD126) is expressed by neoplastic but not normal plasma cells. Blood 63 11090073
1994 Interleukin-1 receptor antagonist (IL-1ra) production by human amnion, chorion, and decidua. American journal of reproductive immunology (New York, N.Y. : 1989) 61 7945810
2019 Metformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells. Leukemia 58 30988378
2017 IL-6R/STAT3/miR-204 feedback loop contributes to cisplatin resistance of epithelial ovarian cancer cells. Oncotarget 56 28388577
2022 Dissecting the IL-6 pathway in cardiometabolic disease: A Mendelian randomization study on both IL6 and IL6R. British journal of clinical pharmacology 54 34931349
2020 SLAMF7 and IL-6R define distinct cytotoxic versus helper memory CD8+ T cells. Nature communications 50 33311473
2002 Cerebrospinal fluid and serum protein levels of tumour necrosis factor-alpha (TNF-alpha) interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R gp80) in multiple sclerosis patients. Cytokine 50 12445803
2019 IL6R-STAT3-ADAR1 (P150) interplay promotes oncogenicity in multiple myeloma with 1q21 amplification. Haematologica 47 31413087
2013 IL-1Ra and its delivery strategies: inserting the association in perspective. Pharmaceutical research 47 23794040
2020 Haematopoietic stem cell gene therapy with IL-1Ra rescues cognitive loss in mucopolysaccharidosis IIIA. EMBO molecular medicine 45 32057196
2002 Shedding of the interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts. The Journal of biological chemistry 45 11884403
2018 Differential expression of IL-6/IL-6R and MAO-A regulates invasion/angiogenesis in breast cancer. British journal of cancer 43 29695771
2017 A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains. Journal of Alzheimer's disease : JAD 42 28106546
2018 IL-6/IL-6R pathway is a therapeutic target in chemoresistant ovarian cancer. Tumori 38 30021477
2002 Evidence for the biological modulation of IL-1 activity: the role of IL-1Ra. Clinical and experimental rheumatology 38 14989424
2021 A Potential Role of IL-6/IL-6R in the Development and Management of Colon Cancer. Membranes 37 33923292
1988 Mapping of a cell-binding domain in the cell adhesion molecule gp80 of Dictyostelium discoideum. The Journal of cell biology 35 3182938
2018 Combinatorial Prg4 and Il-1ra Gene Therapy Protects Against Hyperalgesia and Cartilage Degeneration in Post-Traumatic Osteoarthritis. Human gene therapy 34 30070147
1994 Involvement of cell-cell adhesion in the expression of the cell cohesion molecule gp80 in Dictyostelium discoideum. Journal of cell science 34 7962211
2014 PI3K/AKT pathway mediates induction of IL-1RA by TSH in fibrocytes: modulation by PTEN. The Journal of clinical endocrinology and metabolism 32 24840811
2023 Regulatory T cell-derived IL-1Ra suppresses the innate response to respiratory viral infection. Nature immunology 31 37945820
2021 Preclinical development of CD126 CAR-T cells with broad antitumor activity. Blood cancer journal 31 33414408
2021 Acute IL-1RA treatment suppresses the peripheral and central inflammatory response to spinal cord injury. Journal of neuroinflammation 30 33407641
2019 IL-1RA regulates immunopathogenesis during fungal-associated allergic airway inflammation. JCI insight 29 31550242
2016 Classic IL-6R signalling is dispensable for intestinal epithelial proliferation and repair. Oncogenesis 29 27869785
2015 Soluble IL6R represents a miR-34a target: potential implications for the recently identified IL-6R/STAT3/miR-34a feed-back loop. Oncotarget 29 26091352
1995 Cytokines oncostatin M and interleukin 1 regulate the expression of the IL-6 receptor (gp80, gp130). Cytokine 28 8580365
2015 Synthesis of self-assembled IL-1Ra-presenting nanoparticles for the treatment of osteoarthritis. Journal of biomedical materials research. Part A 27 26507256
2021 Interleukin-1Ra (Il-1Ra) and serum cortisol level relationship in horse as dynamic adaptive response during physical exercise. Veterinary immunology and immunopathology 26 34922262
2015 Exogenous expression of IL-1Ra and TGF-β1 promotes in vivo repair in experimental rabbit osteoarthritis. Scandinavian journal of rheumatology 26 26079860
2014 The IL-6/IL-6R/sgp130 system and Th17 associated cytokines in patients with gestational diabetes. Endokrynologia Polska 26 24971916
2024 Immunotherapeutic IL-6R and targeting the MCT-1/IL-6/CXCL7/PD-L1 circuit prevent relapse and metastasis of triple-negative breast cancer. Theranostics 24 38505617
2014 Stroke, IL-1ra, IL1RN, infection and outcome. Neurocritical care 23 24233813
2023 MiR-21-5p protects against ischemic stroke by targeting IL-6R. Annals of translational medicine 22 36819547
2001 Expression of interleukin-6, interleukin-6 receptor (gp80), and the receptor's signal-transducing subunit (gp130) in human normal pituitary glands and pituitary adenomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 22 11504839
1994 Epitope analysis of human IL-6 receptor gp80 molecule with monoclonal antibodies. European cytokine network 22 7524715
2023 Acute IL-6 exposure triggers canonical IL6Ra signaling in hiPSC microglia, but not neural progenitor cells. Brain, behavior, and immunity 21 36781081
2023 Blockade of IL-6R prevents preterm birth and adverse neonatal outcomes. EBioMedicine 21 37944273
2006 Structural requirements for gp80 independence of human herpesvirus 8 interleukin-6 (vIL-6) and evidence for gp80 stabilization of gp130 signaling complexes induced by vIL-6. Journal of virology 21 16973585
1990 A pharmacologically distinct cyclic AMP receptor is responsible for the regulation of gp80 expression in Dictyostelium discoideum. Molecular and cellular biology 21 2162472
2024 P. gingivalis in oral-prostate axis exacerbates benign prostatic hyperplasia via IL-6/IL-6R pathway. Military Medical Research 20 38764065
2022 MiR-520h inhibits viability and facilitates apoptosis of KGN cells through modulating IL6R and the JAK/STAT pathway. Reproductive biology 20 35085910
2022 IL-1Ra gene transfer potentiates BMP2-mediated bone healing by redirecting osteogenesis toward endochondral ossification. Molecular therapy : the journal of the American Society of Gene Therapy 20 36245128
2025 Oncolytic reprogramming of tumor microenvironment shapes CD4 T-cell memory via the IL6ra-Bcl6 axis for targeted control of glioblastoma. Nature communications 19 39885128
2019 VEGFR2 survival and mitotic signaling depends on joint activation of associated C3ar1/C5ar1 and IL-6R-gp130. Journal of cell science 19 30765465
2019 IL-1RA suppresses esophageal cancer cell growth by blocking IL-1α. Journal of clinical laboratory analysis 19 31102307
2016 Circulating Soluble IL-6R but Not ADAM17 Activation Drives Mononuclear Cell Migration in Tissue Inflammation. Journal of immunology (Baltimore, Md. : 1950) 19 27698010
2002 Effect of IL-1ra on human dental pulp cells and pulpal inflammation. International endodontic journal 19 12406373
1998 IL-6 receptor (CD126'IL-6R') expression is increased on monocytes and B lymphocytes in HIV infection. Cellular immunology 19 9878116
1992 Identification of a unique cAMP-response element in the gene encoding the cell adhesion molecule gp80 in Dictyostelium discoideum. The Journal of biological chemistry 19 1326559
2023 IL-1RA promotes oral squamous cell carcinoma malignancy through mitochondrial metabolism-mediated EGFR/JNK/SOX2 pathway. Journal of translational medicine 18 37461111
2022 Classical Signaling and Trans-Signaling Pathways Stimulated by Megalobrama amblycephala IL-6 and IL-6R. International journal of molecular sciences 18 35216135
2019 Are IL1B, IL6 and IL6R Gene Variants Associated with Anterior Cruciate Ligament Rupture Susceptibility? Journal of sports science & medicine 18 30787661
2018 Plasma levels of IL-1Ra are associated with schizophrenia. Psychiatry and clinical neurosciences 18 30375100
2016 The IL6R gene polymorphisms are associated with sIL-6R, IgE and lung function in Chinese patients with asthma. Gene 17 26997259
2013 The association of IL-6 and IL-6R gene polymorphisms with chronic periodontitis in a Chinese population. Oral diseases 17 23433353
2007 The existence of gender difference in IL-1Ra gene polymorphism. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 17 18052726
2024 Inhibition of CSF-1R and IL-6R prevents conversion of cDC2s into immune incompetent tumor-induced DC3s boosting DC-driven therapy potential. Cell reports. Medicine 16 38242119
2023 Constitutive IL-1RA production by modified immune cells protects against IL-1-mediated inflammatory disorders. Science translational medicine 16 37256935
2019 Interleukin-6 Receptor (IL-6R) Expression in Human Gastric Carcinoma and its Clinical Significance. Cancer investigation 16 31328584
2015 CD126 and Targeted Therapy with Tocilizumab in Chronic Lymphocytic Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 16 26712690
1983 Loss and resynthesis of a developmentally regulated membrane protein (gp80) during dedifferentiation and redifferentiation in Dictyostelium. Developmental biology 16 6409694
2025 Targeting p21-Positive Senescent Chondrocytes via IL-6R/JAK2 Inhibition to Alleviate Osteoarthritis. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 15 39853717
2020 CD4+CD126low/- Foxp3+ Cell Population Represents a Superior Subset of Regulatory T Cells in Treating Autoimmune Diseases. Molecular therapy : the journal of the American Society of Gene Therapy 15 32738192
2011 Ten-color flow cytometry reveals distinct patterns of expression of CD124 and CD126 by developing thymocytes. BMC immunology 15 21689450
2008 Impact of polymorphism in IL-1RA gene on the risk of cervical cancer. Archives of gynecology and obstetrics 15 18008080
2008 IL-6R distribution in normal human and cynomolgus monkey tissues. Regulatory toxicology and pharmacology : RTP 15 19010373
2024 Berberine-loaded PLGA nanoparticles alleviate ulcerative colitis by targeting IL-6/IL-6R axis. Journal of translational medicine 14 39448992
2020 Preparation and Evaluation of IL-1ra-Loaded Dextran/PLGA Microspheres for Inhibiting Periodontal Inflammation In Vitro. Inflammation 14 31664694
2017 Role of IL-1ra and Granzyme B as biomarkers in active Crohn's disease patients. Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals 14 28972805
1999 CD130 rather than CD126 expression is associated with disease activity in multiple myeloma. British journal of haematology 13 10460618
2023 Association of Polymorphisms of IL-6 Pathway Genes (IL6, IL6R and IL6ST) with COVID-19 Severity in an Amazonian Population. Viruses 12 37243282
2004 [IL-1Ra: its role in rheumatoid arthritis]. Reumatismo 12 15201939
1999 Interleukin-6 receptor signaling. I. gp80 and gp130 receptor interaction in the absence of interleukin-6. European cytokine network 12 10210772
2022 Optimization of IL-1RA structure to achieve a smaller protein with a higher affinity to its receptor. Scientific reports 11 35523814
2022 Upregulation of hsa_circ_0004812 promotes COVID-19 cytokine storm via hsa-miR-1287-5p/IL6R, RIG-I axis. Journal of clinical laboratory analysis 11 35989496
2021 Prenatal administration of IL-1Ra attenuate the neurodevelopmental impacts following non-pathogenic inflammation during pregnancy. Scientific reports 11 34862457
2025 Anti-IL-6R Ab tocilizumab to treat paraneoplastic inflammatory syndrome of solid cancers. ESMO open 10 39754984
2022 miR-451a targeting IL-6R activates JAK2/STAT3 pathway, thus regulates proliferation and apoptosis of multiple myeloma cells. Journal of musculoskeletal & neuronal interactions 10 35642704
2019 Discovery of IL-6 and Development of Anti-IL-6R Antibody. The Keio journal of medicine 10 31875623

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