Affinage

Showing IL6ST — GP130 is a alias.

IL6ST

Interleukin-6 receptor subunit beta · UniProt P40189

Length
918 aa
Mass
103.5 kDa
Annotated
2026-06-10
79 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IL6ST encodes GP130, the shared signal-transducing transmembrane receptor subunit of the IL-6 cytokine family that, upon ligand binding, associates with cytokine-specific receptors to activate JAK2/STAT3 signaling (PMID:1475713, PMID:18650419). Cytokine engagement assembles GP130 into receptor complexes that drive STAT3 Y705 phosphorylation, with selective coupling to STAT3 over MAPK/ERK in defined cell contexts such as T cell subsets (PMID:16540526), and signaling also achievable through soluble IL-6R (trans-signaling) versus membrane IL-6R (classic signaling) (PMID:21990364). The membrane-proximal extracellular domains govern cytokine selectivity: structure-guided and molecular-dynamics analyses show that disease variants (N404Y, A517P) increase flexibility of these domains and destabilize hexameric receptor complexes while sparing the trimeric LIF-GP130-LIFR complex, explaining why distinct mutations cause cytokine-selective signaling defects—N404Y abolishes IL-6/IL-11/IL-27/OSM but spares LIF (PMID:28747427), R281Q selectively eliminates IL-11 signaling (PMID:32566365), and combined variants produce IL-6/IL-11-dominated defects (PMID:33771552, PMID:38453915). The soluble GP130 ectodomain (sgp130), including the alternatively polyadenylated sgp130-E10 isoform, acts as a decoy that selectively inhibits IL-6 trans-signaling by binding the IL-6·sIL-6R complex rather than free IL-6, though endogenous sgp130 levels are insufficient to buffer inflammatory IL-6 concentrations (PMID:21990364, PMID:24973212, PMID:29559558). IL6ST causes two human Mendelian disorders: gain-of-function in-frame deletions near the transmembrane domain drive ligand-independent constitutive STAT3 activation that is JAK-inhibitor sensitive (PMID:33517393), and dominant-negative truncations downstream of the transmembrane domain that lack the intracellular recycling motif and STAT3-recruiting tyrosines accumulate at the cell surface to cause autosomal dominant hyper-IgE syndrome (PMID:32207811, PMID:40526438). GP130 abundance is post-transcriptionally controlled by chaperone-mediated autophagy via KFERQ-dependent HSPA8 binding and LAMP2A-mediated lysosomal degradation (PMID:35435804), by K63-linked ubiquitination through FBXO2 that is required for STAT3 activation during decidualization (PMID:41076860), and by IGF2BP3-mediated stabilization of m6A-modified IL6ST mRNA (PMID:41286950), while transcription is driven by FXR, YEATS2-recruited chromatin modifiers, and promoter methylation status in various cancers (PMID:38360812, PMID:40040791, PMID:39821173). Through the GP130/JAK2/STAT3 axis IL6ST contributes to nociceptor TRPA1 regulation (PMID:34252913), context-dependent tumor promotion or senescence-mediated suppression (PMID:39482716, PMID:41286950), and reproductive endometrial signaling (PMID:19060097).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1992 Medium

    Established the foundational identity of GP130 as the signal-transducing component of the IL-6 receptor complex, distinguishing the receptor's ligand-binding from its signaling function.

    Evidence Gene characterization and functional receptor association assays

    PMID:1475713

    Open questions at the time
    • Did not resolve downstream kinase coupling
    • No structural basis for receptor assembly
  2. 2007 Medium

    Showed that single extracellular residues tune GP130 signaling efficacy, establishing that natural variation modulates STAT3 output.

    Evidence Reconstitution of Gly148/Arg148 variants in gp130-null BAF/3 cells with proliferation and pSTAT3 readouts

    PMID:17997171

    Open questions at the time
    • Single polymorphism, no disease link
    • Mechanism of affinity change not structurally resolved
  3. 2008 High

    Defined the structural determinants of GP130's interaction with the IL-6/sIL-6R complex and engineered selective trans-signaling inhibition, separating classic from trans-signaling at the receptor level.

    Evidence 3D structural analysis, NMR of membrane-proximal domain, site-directed mutagenesis, in vitro and mouse inflammation assays

    PMID:18650419

    Open questions at the time
    • Species-specific interactions complicate translation
    • Did not map all selectivity-determining residues
  4. 2011 High

    Resolved the selectivity and concentration-dependence of sgp130 inhibition and identified the colon as a tissue dominated by IL-6 trans-signaling.

    Evidence Quantitative binding studies, proliferation inhibition, tocilizumab comparison, in vivo sgp130Fc mouse experiments

    PMID:21990364

    Open questions at the time
    • Endogenous sgp130 sufficiency not yet quantified
    • Tissue selectivity mechanism unclear
  5. 2014 High

    Identified a novel alternatively polyadenylated soluble isoform sgp130-E10 with selective trans-signaling inhibitory activity, expanding the natural decoy repertoire.

    Evidence Molecular cloning, PBMC expression, Fc-fusion binding and trans-signaling inhibition assays

    PMID:24973212

    Open questions at the time
    • Physiological abundance and regulation of sgp130-E10 unknown
    • In vivo role not tested
  6. 2006 Medium

    Demonstrated cell-type-selective signaling output, with GP130 driving STAT3 but not MAPK/ERK in T cell subsets and minimal expression on regulatory T cells.

    Evidence Flow cytometry and phospho-STAT3/ERK staining in primary human leukocytes

    PMID:16540526

    Open questions at the time
    • Basis for selective pathway coupling unresolved
    • Correlative, not causal for Treg biology
  7. 2017 High

    First demonstrated cytokine-selective human loss-of-function (N404Y), proving a single GP130 residue is differentially required across the cytokine family.

    Evidence Patient genetics and functional signaling assays in patient-derived cells across multiple cytokines

    PMID:28747427

    Open questions at the time
    • Structural basis of selectivity not yet defined at this stage
    • Single-residue, single-family generalization untested
  8. 2020 High

    Defined the dominant-negative mechanism of autosomal dominant hyper-IgE syndrome, showing mutant GP130 lacking the recycling motif and STAT3 tyrosines accumulates at the surface and broadly blocks IL-6 family signaling.

    Evidence Patient genetics across 8 kindreds, mutant overexpression, surface-accumulation flow cytometry, signaling assays in patient cells

    PMID:32207811

    Open questions at the time
    • Precise structural requirements of truncation not yet mapped
    • How surface accumulation suppresses WT signaling not fully resolved
  9. 2020 High

    Established IL-11-selective loss of function (R281Q) with an orthologous mouse model, linking GP130 cytokine selectivity to skeletal/craniofacial phenotypes.

    Evidence Exome sequencing, transfected and primary cell signaling assays, CRISPR knock-in mouse

    PMID:32566365

    Open questions at the time
    • Structural basis for IL-11 selectivity not yet shown
    • Tissue specificity of the defect not fully explained
  10. 2021 High

    Provided the structural mechanism for cytokine selectivity, showing disease variants destabilize hexameric complexes while sparing the trimeric LIF-GP130-LIFR complex via a distinct membrane-proximal interaction.

    Evidence Multi-omic patient sequencing, eight-cytokine signaling assays, molecular dynamics and structural modeling

    PMID:33771552

    Open questions at the time
    • Direct structural confirmation by experimental structure pending at this stage
    • Compound heterozygote rarity limits generalization
  11. 2021 Medium

    Identified mosaic gain-of-function in-frame deletion causing ligand-independent constitutive STAT3 hyperactivation that is pharmacologically reversible with JAK inhibitors.

    Evidence Exome sequencing, pSTAT3 western blot in patient B cells, ruxolitinib/tofacitinib treatment

    PMID:33517393

    Open questions at the time
    • Single patient/lab
    • Structural basis of constitutive activation not resolved here
  12. 2018 High

    Tested the sgp130 buffer hypothesis quantitatively, showing endogenous sgp130 is insufficient to block inflammatory trans-signaling, and that an antibody stabilizing IL-6·sIL-6R can selectively boost trans-signaling.

    Evidence Quantitative ELISA of complexes, single-domain antibody VHH6, functional signaling assays

    PMID:29559558

    Open questions at the time
    • In vivo buffering during disease not measured
    • Generalizability across tissues unknown
  13. 2022 High

    Established GP130 protein abundance as autophagy-regulated, identifying it as a KFERQ/HSPA8/LAMP2A chaperone-mediated autophagy substrate that controls proliferation and migration.

    Evidence LAMP2A knockdown, lysosomal fractionation, HSPA8 co-IP, functional rescue assays

    PMID:35435804

    Open questions at the time
    • KFERQ motif location not explicitly mapped
    • Physiological trigger of GP130 CMA in vivo unknown
  14. 2022 High

    Linked GP130 to nociception by showing it is required for TRPA1 upregulation in uninjured sensory neurons and for mechanical hypersensitivity after nerve injury.

    Evidence Conditional SNS-gp130 knockout, behavioral, electrophysiological and RT-PCR readouts, adenoviral rescue

    PMID:34252913

    Open questions at the time
    • Cytokine driving the neuronal effect not identified
    • Direct GP130-to-Trpa1 transcriptional link not resolved
  15. 2024 High

    Provided cryoEM structures of IL-11 and IL-6 receptor recognition complexes with wild-type and mutant GP130, supporting a 'dimmer switch' model where geometric stringency at the membrane controls signaling.

    Evidence CryoEM structure determination and molecular dynamics simulations

    PMID:38453915

    Open questions at the time
    • Full transmembrane/intracellular signaling geometry not resolved
    • Dynamics of signaling activation not directly visualized
  16. 2024 Medium

    Showed transcriptional control of IL6ST by FXR, coupling nuclear receptor activity to JAK2/STAT3-driven tumor migration and angiogenesis in lung cancer.

    Evidence ChIP, in vitro migration/invasion/angiogenesis assays, in vivo metastasis model, FXR inhibitor

    PMID:38360812

    Open questions at the time
    • Single lab
    • Relative contribution of IL6ST vs IL-6 promoter binding not dissected
  17. 2024 Medium

    Demonstrated context-dependent tumor suppression, where constitutive IL6ST/STAT3 activation in prostate epithelium induces senescence via STAT3/ARF/p53 and recruits cytotoxic T cells.

    Evidence Genetic constitutive IL6ST activation in mouse prostate, transcriptomics, histopathology, senescence assays

    PMID:39482716

    Open questions at the time
    • Single model/lab
    • Determinants of pro- vs anti-tumor outcome unresolved
  18. 2025 High

    Systematically defined the truncation boundaries required for dominant-negative hyper-IgE syndrome, pinpointing loss of the intracellular recycling motif (782-787) and surface accumulation as the mechanism.

    Evidence Comprehensive truncation mutagenesis, surface-accumulation flow cytometry, signaling assays, patient genetics

    PMID:40526438

    Open questions at the time
    • Mechanism by which surface-retained mutant suppresses WT GP130 not fully resolved
  19. 2025 Medium

    Identified FBXO2-mediated K63 ubiquitination as a post-translational requirement for IL6ST/STAT3 activation during decidualization and a target of cadmium toxicity.

    Evidence Co-IP ubiquitination, FBXO2 overexpression rescue, in vitro stromal models, in vivo cadmium mouse model

    PMID:41076860

    Open questions at the time
    • Ubiquitination site on IL6ST not mapped
    • Single lab
  20. 2025 Medium

    Showed chromatin and RNA-level regulation of IL6ST, including YEATS2/TAF15/KAT5-driven H3K27ac promoter activation and IGF2BP3-mediated m6A mRNA stabilization in a STAT3 feedback loop.

    Evidence Co-IP-MS, ChIP, RIP-qPCR, in vitro and in vivo tumor assays

    PMID:40040791 PMID:41286950

    Open questions at the time
    • Single-lab cancer-specific findings
    • Generalizability of feedback loop beyond these tumors untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse post-transcriptional, ubiquitination, and chaperone-mediated autophagy controls of GP130 abundance are integrated with cytokine-specific receptor geometry to set context-dependent STAT3 output in physiology versus disease remains unresolved.
  • No unified model linking abundance regulation to signaling geometry
  • Tissue-specific determinants of pro- vs anti-tumor STAT3 outcomes unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0048018 receptor ligand activity 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 2 GO:0005764 lysosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 3 R-HSA-9612973 Autophagy 1
Partners
FBXO2HSPA8IGF2BP3IL6RLAMP2ALIFR
Complex memberships
IL-6 receptor signaling complex (IL-6/IL-6R/GP130)IL-6·sIL-6R·sgp130 ternary complexLIF-GP130-LIFR trimeric complex

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 GP130 (IL6ST) is a membrane glycoprotein that associates with the IL-6 receptor after ligand binding to potentiate the cytokine response; it functions as the signal-transducing component of the IL-6 receptor complex. Chromosomal localization and gene characterization studies; functional receptor association assays Somatic cell and molecular genetics Medium 1475713
1995 The active IL6ST gene is located at chromosome band 5q11; a nontranscribed pseudogene exists at chromosome band 17p11. Chromosomal localization by fluorescence in situ hybridization and somatic cell genetics Cytogenetics and cell genetics Medium 7736792
2008 Structure-guided mutagenesis of gp130 identified amino acid residues in the extracellular domain (particularly in the cytokine-binding domain) that, when mutated, increase binding affinity to the IL-6/sIL-6R complex. A triple mutein (T102Y/Q113F/N114L) showed additive improvement in binding affinity and selective inhibition of IL-6 trans-signaling without affecting classic signaling, demonstrating species specificity of these interactions. 3D structural analysis of gp130 in complex with IL-6 and sIL-6R, NMR analysis of membrane-proximal domain, site-directed mutagenesis, in vitro cell proliferation assays, acute phase gene expression assays, mouse model of acute inflammation The Journal of biological chemistry High 18650419
2011 Soluble gp130 (sgp130) specifically inhibits IL-6 trans-signaling via sIL-6R but, under conditions of molar excess of sIL-6R over IL-6, can also trap free IL-6 into IL-6·sIL-6R·sgp130 ternary complexes, thereby inhibiting classic signaling. In vivo, sgp130Fc blocked IL-6 signaling in the colon but not in liver and lung, identifying the colon as a prominent target of IL-6 trans-signaling. Quantitative binding studies, cell proliferation inhibition assays, comparison with anti-IL-6R antibody tocilizumab, in vivo mouse experiments with sgp130Fc The Journal of biological chemistry High 21990364
2014 Alternative intronic polyadenylation in intron 10 of the gp130 (IL6ST) transcript generates a novel soluble isoform, sgp130-E10 (70–80 kDa). The sgp130-E10 protein binds to the IL-6/sIL-6R complex but not to IL-6 alone, and specifically inhibits IL-6 trans-signaling. Molecular cloning, expression in human PBMCs, recombinant protein production as Fc-fusion, binding assays, IL-6 trans-signaling inhibition assays The Journal of biological chemistry High 24973212
2017 A homozygous missense mutation in IL6ST (p.N404Y) causes loss of IL-6, IL-11, IL-27, and OSM signaling through GP130 while largely preserving LIF signaling, demonstrating that the N404 residue is selectively required for a subset of GP130 cytokine responses. Patient genetic analysis, functional signaling assays in patient-derived cells, cytokine stimulation experiments The Journal of experimental medicine High 28747427
2007 A non-conservative polymorphism in gp130 (Gly148Arg) reduces cellular proliferation and STAT3 phosphorylation in response to gp130 stimulation, demonstrating that this residue influences GP130 signaling efficacy. Structural modeling, stable transfection of BAF/3 cells lacking endogenous gp130 with Gly148 or Arg148 variants, IL-6 stimulation proliferation assays, STAT3 phosphorylation assays Regulatory peptides Medium 17997171
2018 Quantitative analysis demonstrated that at inflammatory IL-6 concentrations, most IL-6 remains free and uncomplexed with sIL-6R or sgp130, indicating that endogenous sgp130 levels in blood are insufficient to block IL-6 trans-signaling. A single-domain antibody (VHH6) that stabilizes IL-6·sIL-6R complexes drives free IL-6 into complexes and boosts trans-signaling without affecting classic signaling. Quantitative ELISA measurement of IL-6·sIL-6R and IL-6·sIL-6R·sgp130 complexes, single-domain antibody (VHH6) experiments, functional signaling assays The Journal of biological chemistry High 29559558
2020 Dominant-negative (DN) truncating mutations in IL6ST cause autosomal dominant hyper-IgE syndrome. The mutant GP130 proteins lack the intracellular recycling motif and all four STAT3-recruiting tyrosine residues; they accumulate at the cell surface and are loss-of-function and dominant-negative for cellular responses to IL-6, IL-11, LIF, and OSM. Patient heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Patient genetic analysis, overexpression of mutant alleles, flow cytometry for cell surface accumulation, functional signaling assays in patient leukocytes and fibroblasts, comparison with STAT3-deficient patients The Journal of experimental medicine High 32207811
2020 A homozygous variant in IL6ST (p.R281Q) causes selective loss of IL-11 signaling through GP130 without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, or CNTF signaling, both in vitro in transfected cell lines and patient-derived primary cells, and in vivo in a knock-in mouse model (Il6st p.R279Q) which shows reduced litter size, facial synostosis and teeth abnormalities. Exome sequencing, transfected cell line signaling assays, primary patient-derived cell assays, CRISPR/Cas9 genome-edited mouse model Bone research High 32566365
2021 Compound heterozygous missense variants in IL6ST (p.Ala517Pro and p.Gly484_Pro518delinsArg) result in a profound IL-6- and IL-11-dominated signaling defect. Molecular dynamics simulations showed that p.Ala517Pro and p.Asn404Tyr variants increase flexibility of the extracellular membrane-proximal domains of GP130, destabilizing hexameric cytokine receptor complexes while the trimeric LIF-GP130-LIFR complex remains stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site caused additional defective LIF signaling consistent with Stüve-Wiedemann syndrome. Exome, genome, and RNA sequencing; functional signaling assays for IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF; molecular dynamics simulations; structural modeling of GP130 cytokine receptor complexes The Journal of allergy and clinical immunology High 33771552
2021 A mosaic gain-of-function IL6ST variant (Tyr186_Tyr190del, present in ~15–40% of cells) causes constitutive IL-6-independent STAT3 hyperphosphorylation at Tyr705 in patient B cell lymphoblastoid cells. This constitutive GP130 activation can be inhibited by the JAK inhibitors ruxolitinib and tofacitinib. Exome sequencing, western blot for STAT3 phosphorylation in patient EBV-immortalized B cells, JAK inhibitor treatment experiments Human molecular genetics Medium 33517393
2022 IL6ST is a substrate of chaperone-mediated autophagy (CMA): it shows KFERQ-dependent binding to the CMA chaperone HSPA8 and accumulates in isolated lysosomes after CMA stimulation by prolonged starvation. Knockdown of the lysosomal CMA receptor LAMP2A increases IL6ST protein levels without changes in mRNA, and promotes cell proliferation and migration in an IL6ST-dependent manner. LAMP2A knockdown, lysosomal fractionation, HSPA8 co-IP, KFERQ motif mutagenesis (implied), cell proliferation and migration assays Autophagy High 35435804
2022 GP130/IL6ST is required for TRPA1 upregulation in uninjured (but not injured) sensory neurons after spared nerve injury. Conditional depletion of gp130 in Nav1.8-expressing neurons (SNS-gp130-/- mice) prevented mechanical hypersensitivity after spared nerve injury and reduced Trpa1 mRNA in sensory neurons; adenoviral re-expression of gp130 in vitro partially restored Trpa1 levels. Conditional knockout mouse model (SNS-gp130-/-), von Frey behavioral testing, ex vivo skin-nerve electrophysiology, RT-PCR for Trpa1 mRNA, adenoviral gp130 re-expression, cinnamaldehyde responsiveness assays Pain High 34252913
2024 CryoEM structures of the IL-11 receptor recognition complex (and an IL-11 complex with a disease-associated mutant gp130) reveal how differences in gp130-binding interfaces drive signaling outcomes. Disease-associated IL6ST variants increase flexibility and distance between extracellular domains of GP130; however, distances converge as the transmembrane helix exits the membrane, suggesting a stringency in geometry for signaling consistent with a dimmer switch mode of action. CryoEM structure determination of IL-11 and IL-6 complexes with wild-type and mutant gp130, molecular dynamics simulations Nature communications High 38453915
2024 FXR (farnesoid X receptor) directly binds to the promoters of IL-6ST and IL-6 genes and upregulates their transcription, thereby activating the Jak2/STAT3 signaling pathway to promote tumor migration, invasion, and angiogenesis in non-small cell lung cancer. Chromatin immunoprecipitation (ChIP) assay demonstrating FXR binding to IL-6ST and IL-6 promoters, in vitro migration/invasion/angiogenesis assays, in vivo mouse metastasis model, natural FXR inhibitor (Z-guggulsterone) experiments Cell death & disease Medium 38360812
2024 Cell-autonomous constitutive activation of IL6ST signaling in prostate epithelial cells triggers STAT3 signaling and induces senescence via the STAT3/ARF/p53 axis, recruits cytotoxic T-cells, and suppresses tumor growth in a Pten-deficient prostate cancer mouse model. Genetic constitutive activation of IL6ST in prostate epithelium in vivo mouse model, transcriptomic analysis, multiplex histopathological analysis, senescence assays Molecular cancer Medium 39482716
2025 Truncating IL6ST variants causing dominant-negative hyper-IgE syndrome require premature termination downstream of amino acid F641 (end of transmembrane domain) for LOF and dominant-negative effects. The dominant-negative mechanism operates through accumulation of mutant GP130 on the cell surface due to absence of the recycling motif (positions 782–787). The most upstream truncation linked to HIES was p.K702Sfs7*. Comprehensive mutagenesis screening of IL6ST truncation variants, flow cytometry for cell surface accumulation, functional signaling assays, patient genetic analysis JCI insight High 40526438
2025 FBXO2 promotes K63-linked ubiquitination of IL6ST, which is required for STAT3 signaling activation during decidualization. Cadmium exposure downregulates FBXO2, reducing IL6ST K63-ubiquitination and suppressing the IL6ST/STAT3 signaling axis, impairing decidualization markers (PRL, IGFBP1, FOXO1). Co-IP for ubiquitination, FBXO2 overexpression rescue of Cd-induced suppression, in vitro stromal cell models, in vivo Cd-exposed mouse model, western blotting Ecotoxicology and environmental safety Medium 41076860
2025 YEATS2 recruits TAF15 and KAT5 to the promoter region of IL6ST to enhance H3K27ac enrichment, thereby transcriptionally activating IL6ST expression, which promotes NF-κB signaling and malignant progression in esophageal squamous cell carcinoma. Co-IP-based mass spectrometry, chromatin immunoprecipitation (ChIP) for YEATS2 and H3K27ac at IL6ST promoter, in vitro and in vivo proliferation/migration assays Frontiers in cell and developmental biology Medium 40040791
2025 IGF2BP3 recognizes and stabilizes m6A-modified IL6ST mRNA, leading to increased IL6ST protein and activation of the JAK2/STAT3 pathway. STAT3, in turn, transcriptionally activates IGF2BP3, forming a positive feedback loop that promotes colorectal cancer progression. RIP-qPCR demonstrating IGF2BP3 binding to IL6ST mRNA, western blotting, RT-qPCR, animal tumor models, STAT3 transcriptional regulation assays Journal of translational medicine Medium 41286950
2006 GP130 (CD130) expression on CD4+CD25- T cells correlates with STAT3 phosphorylation upon IL-6 or hyper-IL-6 stimulation, while CD25high regulatory T cells express little CD130 and show reduced STAT3 phosphorylation. GP130 dimerization does not activate MAPK ERK1/2 in these cells, demonstrating selective STAT3 but not MAPK activation by GP130 in T cell subsets. Flow cytometry for CD126/CD130 expression, phospho-STAT3 and phospho-ERK1/2 intracellular staining, IL-6 and hyper-IL-6 stimulation of human blood, tonsil, and spleen leukocytes International immunology Medium 16540526
2008 LIF signals through LIFR and its co-receptor IL6ST in the ovine uterus. IL6ST mRNA and protein are localized primarily to the middle-to-deep glandular epithelium of the endometrium. Progesterone and interferon tau regulate IL6ST expression in a stage- and cell-specific manner. LIF stimulation of mononuclear trophectoderm and glandular epithelial cells elicits increases in phosphorylated STAT3 and MAPK3/1. In situ hybridization and immunohistochemistry for LIFR and IL6ST, ovariectomized ewe hormone treatment experiments, LIF stimulation with phospho-STAT3 and phospho-MAPK western blotting Reproduction (Cambridge, England) Medium 19060097
2022 IL6ST (gp130) activates the JAK2/STAT3 signaling pathway in cardiomyocytes; knockdown of IL6ST eliminates the mitochondrial ROS scavenging effect and autophagy-promoting effect of silibinin on doxorubicin-injured cardiomyocytes. Molecular docking predicts silibinin binds IL6ST (affinity ≤ -7.0 kcal/mol). IL6ST siRNA knockdown in AC16 cardiomyocytes, western blot for pathway activation, autophagy assays, ROS measurement, molecular docking European journal of pharmacology Low 35839932
2025 Hypomethylation of the IL6ST promoter in endometriosis leads to elevated IL6ST expression and activation of the JAK2/STAT3 pathway in endometrial stromal cells, promoting their viability, invasion, and resistance to apoptosis. JAK2/STAT3 inhibitor WP1066 reversed the proliferative and invasive effects of IL6ST overexpression. IHC, methylation analysis by bisulfite sequencing, stable transfection of IL6ST overexpression plasmid, CCK-8, Transwell, TUNEL assays, western blot for p-JAK2, p-STAT3, HIF-1α, VEGF PloS one Medium 39821173

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 The balance of interleukin (IL)-6, IL-6·soluble IL-6 receptor (sIL-6R), and IL-6·sIL-6R·sgp130 complexes allows simultaneous classic and trans-signaling. The Journal of biological chemistry 195 29559558
2017 A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. The Journal of experimental medicine 162 28747427
2011 Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor. The Journal of biological chemistry 146 21990364
2020 Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome. The Journal of experimental medicine 116 32207811
2006 Differential expression of CD126 and CD130 mediates different STAT-3 phosphorylation in CD4+CD25- and CD25high regulatory T cells. International immunology 90 16540526
2018 Selective loss of function variants in IL6ST cause Hyper-IgE syndrome with distinct impairments of T-cell phenotype and function. Haematologica 79 30309848
1999 CSF and serum levels of soluble interleukin-6 receptors (sIL-6R and sgp130), but not of interleukin-6 are altered in multiple sclerosis. Journal of neuroimmunology 70 10505978
2008 Structure-guided optimization of the interleukin-6 trans-signaling antagonist sgp130. The Journal of biological chemistry 60 18650419
2018 Evaluation of interleukin-6 and its soluble receptor components sIL-6R and sgp130 as markers of inflammation in inflammatory bowel diseases. International journal of colorectal disease 51 29748708
2022 Impaired degradation of YAP1 and IL6ST by chaperone-mediated autophagy promotes proliferation and migration of normal and hepatocellular carcinoma cells. Autophagy 49 35435804
2019 The IL-6-neutralizing sIL-6R-sgp130 buffer system is disturbed in patients with type 2 diabetes. American journal of physiology. Endocrinology and metabolism 45 31237452
2021 lncRNA MALAT1 Promotes Renal Fibrosis in Diabetic Nephropathy by Targeting the miR-2355-3p/IL6ST Axis. Frontiers in pharmacology 43 33995063
2019 MiR-223-3p Alleviates Vascular Endothelial Injury by Targeting IL6ST in Kawasaki Disease. Frontiers in pediatrics 40 31396494
2016 Increased levels of IL-6, sIL-6R, and sgp130 in the aqueous humor and serum of patients with diabetic retinopathy. Molecular vision 37 27563232
2023 α-Synuclein Induces Neuroinflammation Injury through the IL6ST-AS/STAT3/HIF-1α Axis. International journal of molecular sciences 34 36674945
2019 miR-188-5p suppresses cellular proliferation and migration via IL6ST: A potential noninvasive diagnostic biomarker for breast cancer. Journal of cellular physiology 34 31650530
2015 Circulating levels of interleukin 6 soluble receptor and its natural antagonist, sgp130, and the risk of myocardial infarction. Atherosclerosis 34 25910182
2001 Investigation of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130) in sera of cancer patients. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 33 11669502
2014 Alternative intronic polyadenylation generates the interleukin-6 trans-signaling inhibitor sgp130-E10. The Journal of biological chemistry 31 24973212
2009 An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease. Clinical and experimental immunology 31 19438606
2021 Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome. The Journal of allergy and clinical immunology 29 33771552
2022 Silibinin eliminates mitochondrial ROS and restores autophagy through IL6ST/JAK2/STAT3 signaling pathway to protect cardiomyocytes from doxorubicin-induced injury. European journal of pharmacology 27 35839932
2014 The IL-6/IL-6R/sgp130 system and Th17 associated cytokines in patients with gestational diabetes. Endokrynologia Polska 26 24971916
2008 Progesterone and interferon tau regulate leukemia inhibitory factor receptor and IL6ST in the ovine uterus during early pregnancy. Reproduction (Cambridge, England) 26 19060097
2021 Mosaic IL6ST variant inducing constitutive GP130 cytokine receptor signaling as a cause of neonatal onset immunodeficiency with autoinflammation and dysmorphy. Human molecular genetics 25 33517393
2020 A variant in IL6ST with a selective IL-11 signaling defect in human and mouse. Bone research 24 32566365
2014 A study of genes encoding cytokines (IL6, IL10, TNF), cytokine receptors (IL6R, IL6ST), and glucocorticoid receptor (NR3C1) and susceptibility to bronchopulmonary dysplasia. BMC medical genetics 24 25409741
1997 IL-6 and soluble IL-6 receptors (sIL-6R and sgp130) in human pleural effusions: massive IL-6 production independently of underlying diseases. Clinical and experimental immunology 24 9010274
2007 A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population. Regulatory peptides 22 17997171
2008 A polymorphism at the IL6ST (gp130) locus is associated with traits of the metabolic syndrome. Obesity (Silver Spring, Md.) 19 18223637
2024 Farnesoid X receptor promotes non-small cell lung cancer metastasis by activating Jak2/STAT3 signaling via transactivation of IL-6ST and IL-6 genes. Cell death & disease 18 38360812
2020 PLXNC1 Enhances Carcinogenesis Through Transcriptional Activation of IL6ST in Gastric Cancer. Frontiers in oncology 17 32117710
2023 New Dominant-Negative IL6ST Variants Expand the Immunological and Clinical Spectrum of GP130-Dependent Hyper-IgE Syndrome. Journal of clinical immunology 15 37273120
2017 Circulating levels of sgp130 and sex hormones in male patients with coronary atherosclerotic disease. Atherosclerosis 15 29028483
2022 Genetic and functional evidence for gp130/IL6ST-induced transient receptor potential ankyrin 1 upregulation in uninjured but not injured neurons in a mouse model of neuropathic pain. Pain 14 34252913
1995 Human gp130 transducer chain gene (IL6ST) is localized to chromosome band 5q11 and possesses a pseudogene on chromosome band 17p11. Cytogenetics and cell genetics 14 7736792
2024 Cell-autonomous IL6ST activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment. Molecular cancer 13 39482716
2020 Analysis of the genetic variants associated with circulating levels of sgp130. Results from the IMPROVE study. Genes and immunity 13 31932740
2020 Increased levels of the soluble oncostatin M receptor (sOSMR) and glycoprotein 130 (sgp130) in systemic sclerosis patients and associations with clinical parameters. Immunobiology 13 32517886
2011 Lack of association of IL6R rs2228145 and IL6ST/gp130 rs2228044 gene polymorphisms with cardiovascular disease in patients with rheumatoid arthritis. Tissue antigens 13 21981268
1999 CD130 rather than CD126 expression is associated with disease activity in multiple myeloma. British journal of haematology 13 10460618
2023 miR-223-3p mediates the diabetic kidney disease progression by targeting IL6ST/STAT3 pathway. Biochemical and biophysical research communications 12 36731227
2023 Association of Polymorphisms of IL-6 Pathway Genes (IL6, IL6R and IL6ST) with COVID-19 Severity in an Amazonian Population. Viruses 12 37243282
2002 Effect of IL-18 on the release of IL-6 and its soluble receptors: sIL-6Ralpha and sgp130 by human neutrophils. Immunological investigations 12 12472176
2022 Genomic Multiple Sclerosis Risk Variants Modulate the Expression of the ANKRD55-IL6ST Gene Region in Immature Dendritic Cells. Frontiers in immunology 11 35111166
2020 Associations between the IL-6-neutralizing sIL-6R-sgp130 buffer system and coronary artery disease in postmenopausal women. Annals of translational medicine 10 32355823
2024 Structural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency. Nature communications 9 38453915
2022 CircUBXN7 suppresses cell proliferation and facilitates cell apoptosis in lipopolysaccharide-induced cell injury by sponging miR-622 and regulating the IL6ST/JAK1/STAT3 axis. The international journal of biochemistry & cell biology 9 36257578
1992 Chromosomal localization of the IL-6 receptor signal transducing subunit, gp130 (IL6ST). Somatic cell and molecular genetics 9 1475713
2017 Association of IL6ST (gp130) Polymorphism with Functional Outcome Following Spontaneous Intracerebral Hemorrhage. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 8 28964648
2022 Variation in IL6ST cytokine family function and the potential of IL6 trans-signalling in ERα positive breast cancer cells. Cellular signalling 7 36565897
2021 New tale on LianHuaQingWen: IL6R/IL6/IL6ST complex is a potential target for COVID-19 treatment. Aging 7 34731090
2010 Map3k1, Il6st, Gzmk, and Hspb3 gene coexpression network in the mechanism of freezing reaction in mice. Journal of neuroscience research 7 21162133
2025 miR-224-5p Suppresses Non-Small Cell Lung Cancer via IL6ST-Mediated Regulation of the JAK2/STAT3 Pathway. Thoracic cancer 6 39840666
2014 Low incidence of IL6ST (gp130) mutations in exon 6 in lung cancer of a Chinese cohort. Cancer genetics 6 25242236
2005 The serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble gp130 (sgp130) in different tumour stages. Correlation between the two parameters in progression of malignancy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 6 16202558
2025 Hypomethylation of IL6ST promotes development of endometriosis by activating JAK2/STAT3 signaling pathway. PloS one 5 39821173
2025 YEATS2 promotes malignant phenotypes of esophageal squamous cell carcinoma via H3K27ac activated-IL6ST. Frontiers in cell and developmental biology 5 40040791
2024 Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors. Frontiers in cell and developmental biology 5 38469154
2024 IL6ST: A Novel Therapeutic Target for Managing and Treating Colorectal Cancer Via Ferroptosis. The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology 5 39344518
2013 No evidence of association between functional polymorphisms located within IL6R and IL6ST genes and Henoch-Schönlein purpura. Tissue antigens 5 24498998
2003 Role of interleukin-15 and interleukin-18 in the secretion of sIL-6R and sgp130 by human neutrophils. Mediators of inflammation 5 12857602
2018 Decreased levels of the serum inflammatory biomarkers, sGP130, IL-6, sCRP and BAFF, are associated with increased likelihood of AIDS related Kaposi's sarcoma in men who have sex with men. Cancer research frontiers 4 33521162
2006 [The role of IL-6/sIL-6R complex and its natural inhibitor sgp130 in modulation of inflammatory process]. Postepy biochemii 4 17078509
2023 Decreased Serum Levels of Soluble Oncostatin M Receptor (sOSMR) and Glycoprotein 130 (sgp130) in Patients with Coronary Artery Disease. Arquivos brasileiros de cardiologia 3 37098986
2012 No evidence of association between functional polymorphisms located within IL6R and IL6ST genes and systemic sclerosis. Tissue antigens 3 22742541
2024 Circular RNA circPHF16 enhances IL-17A expression and secretion by sequestering miR-378a-3p to activate the IL6ST axis in Graves' disease. Cytokine 2 38963941
2023 Associations between serum estradiol and IL-6/sIL-6R/sgp130 complex in female patients with major depressive disorder. BMC psychiatry 2 37828513
2025 Cadmium disrupts IL6ST/STAT3 signaling involving FBXO2 in decidualization: Environmental trigger of spontaneous abortion. Ecotoxicology and environmental safety 1 41076860
2025 Positive feedback loop of IGF2BP3/IL6ST/STAT3 facilitates malignant progression in colorectal cancer. Journal of translational medicine 1 41286950
2024 MiR362-3p Alleviates Osteosarcoma by Regulating the IL6ST/JAK2/STAT3 Pathway in Vivo and in Vitro. Technology in cancer research & treatment 1 39051528
2026 ANXA2, DBN1, ZNF385D, and IL6ST: Endothelial cell biomarkers linking atherosclerosis progression to immune microenvironment dysregulation. Clinical and experimental hypertension (New York, N.Y. : 1993) 0 41655191
2026 IL-11-IL6ST-STAT3 signaling defines a convergent inflammatory axis in esophageal cancer subtypes. Scientific reports 0 41936612
2025 Fine mapping of heterozygous IL6ST nonsense variants underlying autosomal dominant hyper-IgE syndrome. JCI insight 0 40526438
2025 A fetal case of Stüve-Wiedemann syndrome due to a novel homozygous truncating variant in IL6ST. European journal of medical genetics 0 40835206
2025 IL6ST participates in the development of adolescent idiopathic scoliosis by regulating bone marrow mesenchymal stem cells. Communications biology 0 41006753
2024 Overexpression of MiR-188-5p Downregulates IL6ST/STAT3/ NLRP3 Pathway to Ameliorate Neuron Injury in Oxygen-glucose Deprivation/Reoxygenation. Current neurovascular research 0 38778610
2013 [Il6st gene mRNA and gp130 protein distribution in the brain structures in mice differing in exagerrated freezing reaction (catalepsy)]. Molekuliarnaia biologiia 0 23888778
2000 [Examination and evaluation of sIL-6R, sgp130 in serum in patients with chronic hepatopathy]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology 0 10861111

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