IL6ST

Summary

IL6ST (interleukin 6 cytokine family signal transducer, HGNC:6021) is a protein-coding gene on chromosome 5q11.2, encoding Interleukin-6 receptor subunit beta (P40189). Signal-transducing molecule.

The protein encoded by this gene is a signal transducer shared by many cytokines, including interleukin 6 (IL6), ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), and oncostatin M (OSM). This protein functions as a part of the cytokine receptor complex. The activation of this protein is dependent upon the binding of cytokines to their receptors. vIL6, a protein related to IL6 and encoded by the Kaposi sarcoma-associated herpesvirus, can bypass the interleukin 6 receptor (IL6R) and directly activate this protein. Knockout studies in mice suggest that this gene plays a critical role in regulating myocyte apoptosis. Alternatively spliced transcript variants have been described. A related pseudogene has been identified on chromosome 17.

Source: NCBI Gene 3572 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyper-IgE recurrent infection syndrome 4, autosomal recessive (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 647 total — 16 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 90
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types
• MANE Select transcript: NM_002184

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6021
Approved symbol	IL6ST
Name	interleukin 6 cytokine family signal transducer
Location	5q11.2
Locus type	gene with protein product
Status	Approved
Aliases	GP130, CD130, sGP130, IL-6RB
Ensembl gene	ENSG00000134352
Ensembl biotype	protein_coding
OMIM	600694
Entrez	3572

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 18 protein_coding, 9 nonsense_mediated_decay, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000381286, ENST00000381293, ENST00000381294, ENST00000381298, ENST00000423954, ENST00000502326, ENST00000503773, ENST00000506241, ENST00000522633, ENST00000523039, ENST00000577363, ENST00000583149, ENST00000651614, ENST00000698638, ENST00000698639, ENST00000698640, ENST00000698641, ENST00000698642, ENST00000698643, ENST00000698644, ENST00000698645, ENST00000698646, ENST00000698647, ENST00000698648, ENST00000698649, ENST00000868545, ENST00000868546, ENST00000868547, ENST00000868548, ENST00000971039, ENST00000971040, ENST00000971041

RefSeq mRNA: 8 — MANE Select: NM_002184 NM_001190981, NM_001364275, NM_001364276, NM_001364277, NM_001364278, NM_001364279, NM_002184, NM_175767

CCDS: CCDS3971, CCDS47209, CCDS54856, CCDS93710, CCDS93711, CCDS93712

Canonical transcript exons

ENST00000381298 — 17 exons

Exon	Start	End
ENSE00000914147	55963352	55963506
ENSE00000914150	55964146	55964312
ENSE00000914153	55968276	55968396
ENSE00000914155	55969550	55969855
ENSE00001006585	55960402	55960561
ENSE00001488109	55935095	55941819
ENSE00001488122	55982724	55982811
ENSE00003469421	55947493	55947589
ENSE00003520944	55951464	55951604
ENSE00003528569	55957209	55957291
ENSE00003536524	55954810	55954992
ENSE00003541462	55951929	55952075
ENSE00003619234	55956025	55956235
ENSE00003651066	55942670	55942751
ENSE00003680337	55952250	55952351
ENSE00003691045	55976215	55976293
ENSE00003842589	55994784	55994963

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 96.3172 / max 831.1343, expressed in 1810 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61725	90.0067	1810
61724	2.5220	944
61717	1.3849	486
61723	1.0146	377
61715	0.6893	321
61722	0.3305	157
61718	0.2755	138
61726	0.0936	26

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
parietal pleura	UBERON:0002400	99.85	gold quality
pleura	UBERON:0000977	99.79	gold quality
germinal epithelium of ovary	UBERON:0001304	99.78	gold quality
visceral pleura	UBERON:0002401	99.77	gold quality
seminal vesicle	UBERON:0000998	99.72	gold quality
caput epididymis	UBERON:0004358	99.70	gold quality
cauda epididymis	UBERON:0004360	99.69	gold quality
superficial temporal artery	UBERON:0001614	99.68	gold quality
pericardium	UBERON:0002407	99.67	gold quality
mammary duct	UBERON:0001765	99.65	gold quality
lower lobe of lung	UBERON:0008949	99.61	gold quality
urethra	UBERON:0000057	99.58	gold quality
trigeminal ganglion	UBERON:0001675	99.56	gold quality
epithelium of mammary gland	UBERON:0003244	99.56	gold quality
corpus epididymis	UBERON:0004359	99.55	gold quality
tibia	UBERON:0000979	99.51	gold quality
calcaneal tendon	UBERON:0003701	99.47	gold quality
dorsal root ganglion	UBERON:0000044	99.44	gold quality
choroid plexus epithelium	UBERON:0003911	99.44	gold quality
vena cava	UBERON:0004087	99.40	gold quality
synovial joint	UBERON:0002217	99.39	gold quality
subthalamic nucleus	UBERON:0001906	99.31	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.31	gold quality
lateral globus pallidus	UBERON:0002476	99.30	gold quality
cartilage tissue	UBERON:0002418	99.23	gold quality
skin of hip	UBERON:0001554	99.22	gold quality
epithelium of nasopharynx	UBERON:0001951	99.18	gold quality
superior vestibular nucleus	UBERON:0007227	99.17	gold quality
corpus callosum	UBERON:0002336	99.16	gold quality
saphenous vein	UBERON:0007318	99.15	gold quality

Single-cell (SCXA)

Detected in 19 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	1262.66
E-HCAD-24	yes	1197.08
E-MTAB-6701	yes	71.63
E-MTAB-10553	yes	55.35
E-MTAB-10287	yes	44.74
E-CURD-122	yes	41.00
E-CURD-119	yes	26.73
E-CURD-46	yes	23.26
E-HCAD-9	yes	22.64
E-HCAD-4	yes	20.18
E-MTAB-9543	yes	15.76
E-CURD-112	yes	12.04
E-HCAD-1	yes	9.16
E-MTAB-6678	yes	8.90
E-MTAB-9067	yes	7.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, JAK1, JUN, STAT1, STAT3, STAT5A, STAT5B

miRNA regulators (miRDB)

269 targeting IL6ST, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821

Literature-anchored findings (GeneRIF, showing 40)

• detection in pericardial fluid in coronary pathologies (PMID:11781191)
• regulation of surface expression by janus kinase 1 (PMID:11786531)
• The cytoplasmic domain of gp130 is involve the induction of c-myc expression and the cell proliferation in Meg-01 cell. (PMID:11877042)
• Shedding of the interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts (PMID:11884403)
• Gp130 and ras mediated signaling in human plasma cell line INA-6: a cytokine-regulated tumor model for plasmacytoma. (PMID:11920233)
• The transcription co-repressor TLE1 interacted with the intracellular region of gpl30 through its Q domain (PMID:12030375)
• gp130 signal transduction is important for the differentiation and maturation of dendritic cells (PMID:12039911)
• Soluble gp130 is up-regulated in the implantation window and shows altered secretion in patients with primary unexplained infertility. (PMID:12161539)
• Diminished GP130 Abundance in congestive heart failure (PMID:12234945)
• PKC delta associates with IL6ST via Stat3 and enhances Stat3-gp130 interaction (PMID:12361954)
• Gp130 activation by soluble IL-6 receptors and IL-6 enhances osteoblastic differfentiation of human bone marrow-derived mesenchymal cells. (PMID:12372336)
• interaction with cyclin-dependent kinase 9 (PMID:12386808)
• There is no significant effect of IL-18 on the release of both soluble receptors of IL-6. (PMID:12472176)
• interactions of CNTFR with LIFR and gp130 in vitro (PMID:12707266)
• Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. (PMID:12782602)
• Data suggest that interleukin-6 activation of gp130 promoted cell division in fibroblasts from patients with idiopathic pulmonary fibrosis (IPF), while IL-11 was mitogenic in both normal and IPF cells. (PMID:12819039)
• a structural model, derived from 3.65 A resolution crystallographic data of the complex between IL-6, the extracellular binding domains of IL-6R, and the extracellular activation and binding domains of gp130 is presented (PMID:12829785)
• involvement of IL-6 in the pathogenesis of liver diseases and suggest a protective role of IL-6/gp130-dependent pathways in nonparenchymal liver cells during fibrosis progression in chronic liver diseases. (PMID:12830005)
• gp130 has a role in glucose-enhanced interleukin-6-induced VEGF165 expression (PMID:14676217)
• CD30 can modify eosinophil survival by causing an extremely rapid and intense induction of apoptosis through a tightly regulated intracellular signaling pathway. (PMID:14764685)
• GP130 together with the cytokine receptor WSX-1 constitutes a functional signal-transducing receptor for IL-27. (PMID:14764690)
• Results suggest that the balance between soluble and membrane-bound gp130 may play an important role in regulating cytokine action necessary for blastocyst implantation and for further interaction between the decidualized endometrium and the trophoblast. (PMID:15133123)
• Two distinct Stat3 signaling pathways emanating from gp130 are utilized in mammary tissue. (PMID:15292206)
• LMO4 interaction modulates the interleukin-6 receptor subunit glycoprotein 130 complex and its signaling (PMID:15677447)
• Endotoxemia up-regulates gp130 expression in vivo and in vitro. (PMID:15721840)
• There is no evidence that mutations in exon 17 of the gp130 gene are involved in the pathogenesis of human inflammatory bowel disease (PMID:15754404)
• RT-PCR analysis showed that glioma tumor cells express oncostatin M receptors. (PMID:15809742)
• A crystal structure of the ligand-binding domains of gp130 in complex with human interleukin-6 (IL-6) and its a-receptor (IL-6Ralpha). (PMID:15895091)
• urokinase-type plasminogen activator induces upregulated expression of the complement anaphylatoxin C5a receptor; this effect is mediated via the interaction of the uPA-specific receptor and gp130 (PMID:15944400)
• The function of IL-6R in the luminal and glandular epithelium might be different from that in the stroma during the implantation period. (PMID:16141642)
• Simultaneous action of two IL-6 binding domains on two gp130 molecules is required to efficiently recruit a fluorescent IL-6 (yellow fluorescent protein-IL-6) to the plasma membrane. (PMID:16254248)
• These findings indicate that the di-leucine motif which directs the internalization of the IL-6 receptor complex also mediates the basolateral sorting of the signal transducer gp130. (PMID:16274960)
• there are tissue-specific differences in IL-6-receptor-gp130-coupled signaling which limit the extent of Stat3 activation and gammaFBG expression during lung inflammation (PMID:16524883)
• decreased expression of GP130 in ejaculated spermatozoa could be associated with low sperm motility in asthenozoospermic men. (PMID:16728717)
• demonstrates the existence of preformed but inactive gp130/leukemia inhibitory factor receptor hetero- and gp130/gp130 homo-dimers (PMID:16774741)
• metastatic melanoma cells could escape this growth control by the epigenetic silencing of oncostatin M receptor beta (PMID:16909117)
• physical evidence of the stabilization of vIL-6-induced gp130 signaling complexes by gp80 (PMID:16973585)
• sOSMR is able to bind OSM and interleukin-31 when associated to soluble gp130 or soluble interleukin-31R, respectively, and to neutralize both cytokine properties (PMID:17028186)
• activation of RankL gene expression by PKA- and gp130-inducers is mediated via common regulatory domains that also served to facilitate the activity of 1,25-(OH)2D3 (PMID:17053039)
• potential role of gp130 receptor ligands as part of a therapeutic strategy to treat obesity. (PMID:17404609)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il6st	ENSMUSG00000021756
rattus_norvegicus	Il6st	ENSRNOG00000013963

Paralogs (23): CRLF1 (ENSG00000006016), IL12RB2 (ENSG00000081985), IL5RA (ENSG00000091181), IL12RB1 (ENSG00000096996), IL27RA (ENSG00000104998), EBI3 (ENSG00000105246), GHR (ENSG00000112964), PRLR (ENSG00000113494), LIFR (ENSG00000113594), LEPR (ENSG00000116678), CSF3R (ENSG00000119535), CNTFR (ENSG00000122756), IL13RA2 (ENSG00000123496), IL13RA1 (ENSG00000131724), IL11RA (ENSG00000137070), OSMR (ENSG00000145623), IL2RG (ENSG00000147168), IL6R (ENSG00000160712), IL23R (ENSG00000162594), IL31RA (ENSG00000164509), IL3RA (ENSG00000185291), CSF2RA (ENSG00000198223), CRLF2 (ENSG00000205755)

Protein

Protein identifiers

Interleukin-6 receptor subunit beta — P40189 (reviewed: P40189)

Alternative names: CDw130, Interleukin-6 signal transducer, Membrane glycoprotein 130, Oncostatin-M receptor subunit alpha

All UniProt accessions (14): A0A0A0N0L2, A0A0A0N0L5, A0A494BZU0, A0A8V8TM11, A0A8V8TMJ4, A0A8V8TMJ9, A0A8V8TNI4, A0A8V8TNI8, A0A8V8TNU5, D6RH03, P40189, Q5FC02, Q5FC05, Q5FC07

UniProt curated annotations — full annotation on UniProt →

Function. Signal-transducing molecule. The receptor systems for IL6, LIF, OSM, CNTF, IL11, CTF1 and BSF3 can utilize IL6ST for initiating signal transmission. Binding of IL6 to IL6R induces IL6ST homodimerization and formation of a high-affinity receptor complex, which activates the intracellular JAK-MAPK and JAK-STAT3 signaling pathways. That causes phosphorylation of IL6ST tyrosine residues which in turn activates STAT3. In parallel, the IL6 signaling pathway induces the expression of two cytokine receptor signaling inhibitors, SOCS1 and SOCS3, which inhibit JAK and terminate the activity of the IL6 signaling pathway as a negative feedback loop. Also activates the yes-associated protein 1 (YAP) and NOTCH pathways to control inflammation-induced epithelial regeneration, independently of STAT3. Acts as a receptor for the neuroprotective peptide humanin as part of a complex with IL27RA/WSX1 and CNTFR. Mediates signals which regulate immune response, hematopoiesis, pain control and bone metabolism. Has a role in embryonic development. Essential for survival of motor and sensory neurons and for differentiation of astrocytes. Required for expression of TRPA1 in nociceptive neurons. Required for the maintenance of PTH1R expression in the osteoblast lineage and for the stimulation of PTH-induced osteoblast differentiation. Required for normal trabecular bone mass and cortical bone composition. Binds to the soluble IL6:sIL6R complex (hyper-IL6), thereby blocking IL6 trans-signaling. Inhibits sIL6R-dependent acute phase response. Also blocks IL11 cluster signaling through IL11R.

Subunit / interactions. Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; associates with the complex IL6:IL6R but does not interact with IL6. Forms heterodimers composed of LIFR and IL6ST (type I OSM receptor) which are activated by LIF and OSM. Also forms heterodimers composed of OSMR and IL6ST (type II receptor) which are activated by OSM but not by LIF. Component of a receptor complex composed of IL6ST/GP130, IL27RA/WSX1 and CNTFR which interacts with the neuroprotective peptide humanin. Interacts with HCK. Interacts with INPP5D/SHIP1. Interacts with SRC and YES. Interacts with ARMH4; this interaction prevents IL6ST protein homodimerization and bridges ARMH4 with IL6R and STAT3 and therefore inhibits phosphorylation of STAT3 at ‘Tyr-705’. (Microbial infection) The homodimer binds two molecules of herpes virus 8/HHV-8 protein vIL-6.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Found in all the tissues and cell lines examined. Expression not restricted to IL6 responsive cells. Expressed in blood serum (at protein level).

Post-translational modifications. Phosphorylation of Ser-782 down-regulates cell surface expression. Heavily N-glycosylated. Glycosylation is required for protein stability and localization in plasma membrane but not for ligand binding.

Disease relevance. Hyper-IgE syndrome 4A, autosomal dominant, with recurrent infections (HIES4A) [MIM:619752] An immunologic disorder characterized by recurrent mainly sino-pulmonary infections associated with increased serum IgE. Some patients have onset of symptoms in early childhood and develop complications, including bronchiectasis or hemoptysis, whereas others have later onset of less severe infections. Immunologic workup usually shows normal leukocyte levels, although some patients may demonstrate alterations in lymphocyte subsets, including T cells. Affected individuals also have variable skeletal abnormalities, including high-arched palate, hyperextensible joints, scoliosis, and bone fractures. The disease is caused by variants affecting the gene represented in this entry. Hyper-IgE syndrome 4B, autosomal recessive, with recurrent infections (HIES4B) [MIM:618523] An immunologic disorder characterized by recurrent infections, mainly affecting the respiratory tract, skin and eye, and skeletal abnormalities including craniosynostosis and scoliosis. Immunologic workup shows increased serum IgE, intermittent eosinophilia, impaired development of certain B- and T-cell populations, as well as impaired acute-phase response. Disease onset is in early childhood. The disease is caused by variants affecting the gene represented in this entry. Stuve-Wiedemann syndrome 2 (STWS2) [MIM:619751] A form of Stuve-Wiedemann syndrome, an autosomal recessive disease characterized by bowing of tubular bones and other skeletal and craniofacial abnormalities, respiratory distress, feeding difficulties, and hyperthermic episodes. Most patients do not survive past infancy. STWS2 patients manifest skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. The disease is caused by variants affecting the gene represented in this entry. Immunodeficiency 94 with autoinflammation and dysmorphic facies (IMD94) [MIM:619750] An autosomal dominant disorder characterized by onset in early infancy, lymphadenopathy, autoinflammation, immunodeficiency with hypogammaglobulinemia, and dysmorphic facial features. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding. The box 1 motif is required for JAK interaction and/or activation.

Induction. LIF and OSM activate the type I OSM receptor while only OSM can activate the type II OSM receptor.

Similarity. Belongs to the type I cytokine receptor family. Type 2 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P40189-1	1	yes
P40189-2	2, GP130-RAPS
P40189-3	3

RefSeq proteins (8): NP_001177910, NP_001351204, NP_001351205, NP_001351206, NP_001351207, NP_001351208, NP_002175, NP_786943 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003529	Hematopoietin_rcpt_Gp130_CS	Conserved_site
IPR003961	FN3_dom	Domain
IPR010457	IgC2-like_lig-bd	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR050379	Type-I_Cytokine_Rcpt	Family

Pfam: PF00041, PF06328, PF25552

UniProt features (126 total): strand 51, sequence variant 15, glycosylation site 10, mutagenesis site 10, helix 9, domain 6, modified residue 6, disulfide bond 5, splice variant 3, region of interest 2, short sequence motif 2, topological domain 2, signal peptide 1, chain 1, compositionally biased region 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
3L5I	X-RAY DIFFRACTION	1.9
1BQU	X-RAY DIFFRACTION	2
1I1R	X-RAY DIFFRACTION	2.4
1PVH	X-RAY DIFFRACTION	2.5
8D74	ELECTRON MICROSCOPY	3.03
3L5J	X-RAY DIFFRACTION	3.04
8D82	ELECTRON MICROSCOPY	3.22
8UPA	X-RAY DIFFRACTION	3.3
7U7N	ELECTRON MICROSCOPY	3.47
8DPS	ELECTRON MICROSCOPY	3.47
8D6A	ELECTRON MICROSCOPY	3.54
8V2A	ELECTRON MICROSCOPY	3.59
3L5H	X-RAY DIFFRACTION	3.6
1P9M	X-RAY DIFFRACTION	3.65
8DPU	X-RAY DIFFRACTION	3.78
8D85	ELECTRON MICROSCOPY	3.81
8D7R	ELECTRON MICROSCOPY	3.9
8V29	ELECTRON MICROSCOPY	3.99
8DPT	ELECTRON MICROSCOPY	4
1BJ8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40189-F1	74.94	0.49

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 661, 667, 782, 789, 829, 839

Disulfide bonds (5): 28–54, 48–103, 134–144, 172–182, 458–466

Glycosylation sites (10): 43, 83, 131, 157, 227, 379, 383, 390, 553, 564

Mutagenesis-validated functional residues (10):

Position	Phenotype
172	induces ligand-independent activation.
186–190	induces ligand-independent activation.
189	does not induce ligand-independent activation.
190	does not induce ligand-independent activation.
215	induces ligand-independent activation.
252	induces ligand-independent activation.
759	refractory to inhibition by socs3.
782	increases cell surface expression.
789–918	results in impaired cytokine-mediated signaling pathway with loss of response to il-6 and il-11. weak response to il-27,
899–918	results in impaired cytokine-mediated signaling pathway with loss of response to il-6 and il-11. weak response to il-27,

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1059683	Interleukin-6 signaling
R-HSA-6788467	IL-6-type cytokine receptor ligand interactions
R-HSA-8984722	Interleukin-35 Signalling
R-HSA-9020956	Interleukin-27 signaling
R-HSA-9958825	Activation of STAT3 by cadherin engagement
R-HSA-110056	MAPK3 (ERK1) activation
R-HSA-112411	MAPK1 (ERK2) activation

MSigDB gene sets: 987 (showing top): PID_SHP2_PATHWAY, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE45365_NK_CELL_VS_BCELL_UP, GGGACCA_MIR133A_MIR133B, GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_INTERLEUKIN_6_SIGNALING, BROWNE_HCMV_INFECTION_4HR_UP, GCM_MAP4K4, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, FREAC2_01, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE

GO Biological Process (30): positive regulation of acute inflammatory response (GO:0002675), positive regulation of adaptive immune response (GO:0002821), glycogen metabolic process (GO:0005977), positive regulation of cell population proliferation (GO:0008284), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of cardiac muscle hypertrophy (GO:0010613), cytokine-mediated signaling pathway (GO:0019221), response to cytokine (GO:0034097), interleukin-11-mediated signaling pathway (GO:0038154), oncostatin-M-mediated signaling pathway (GO:0038165), positive regulation of T cell proliferation (GO:0042102), negative regulation of apoptotic process (GO:0043066), negative regulation of neuron apoptotic process (GO:0043524), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of Notch signaling pathway (GO:0045747), positive regulation of astrocyte differentiation (GO:0048711), leukemia inhibitory factor signaling pathway (GO:0048861), intestinal epithelial cell development (GO:0060576), interleukin-6-mediated signaling pathway (GO:0070102), negative regulation of interleukin-6-mediated signaling pathway (GO:0070104), interleukin-27-mediated signaling pathway (GO:0070106), ciliary neurotrophic factor-mediated signaling pathway (GO:0070120), T-helper 17 cell lineage commitment (GO:0072540), cell surface receptor signaling pathway via STAT (GO:0097696), positive regulation of platelet aggregation (GO:1901731), signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), regulation of Notch signaling pathway (GO:0008593), cell differentiation (GO:0030154)

GO Molecular Function (18): cytokine receptor activity (GO:0004896), ciliary neurotrophic factor receptor activity (GO:0004897), interleukin-6 receptor activity (GO:0004915), interleukin-11 receptor activity (GO:0004921), ciliary neurotrophic factor receptor binding (GO:0005127), coreceptor activity (GO:0015026), growth factor binding (GO:0019838), cytokine binding (GO:0019955), interleukin-11 binding (GO:0019970), protein tyrosine kinase activator activity (GO:0030296), identical protein binding (GO:0042802), interleukin-27 receptor activity (GO:0045509), scaffold protein binding (GO:0097110), leukemia inhibitory factor receptor activity (GO:0004923), oncostatin-M receptor activity (GO:0004924), interleukin-6 receptor binding (GO:0005138), protein binding (GO:0005515), interleukin-6 binding (GO:0019981)

GO Cellular Component (14): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), interleukin-6 receptor complex (GO:0005896), type I oncostatin-M receptor complex (GO:0005900), external side of plasma membrane (GO:0009897), membrane (GO:0016020), dendrite (GO:0030425), neuronal cell body (GO:0043025), signaling receptor complex (GO:0043235), membrane raft (GO:0045121), extracellular exosome (GO:0070062), ciliary neurotrophic factor receptor complex (GO:0070110), cell body (GO:0044297)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Interleukin-6 family signaling	2
Interleukin-12 family signaling	2
RAF-independent MAPK1/3 activation	2
Adherens junctions interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine-mediated signaling pathway	4
cytokine receptor activity	4
protein binding	4
cytokine binding	3
cellular anatomical structure	3
plasma membrane signaling receptor complex	3
interleukin-6-mediated signaling pathway	2
cytokine receptor binding	2
growth factor binding	2
acute inflammatory response	1
regulation of acute inflammatory response	1
positive regulation of inflammatory response	1
adaptive immune response	1
regulation of adaptive immune response	1
positive regulation of immune response	1
energy reserve metabolic process	1
glucan metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
positive regulation of cytokine production	1
vascular endothelial growth factor production	1
regulation of vascular endothelial growth factor production	1
cardiac muscle hypertrophy	1
regulation of cardiac muscle hypertrophy	1
positive regulation of muscle hypertrophy	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
response to peptide	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of T cell activation	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
osteoblast differentiation	1

Protein interactions and networks

STRING

1307 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL6ST	IL6	P05231	997
IL6ST	IL6R	P08887	988
IL6ST	IL27RA	Q6UWB1	986
IL6ST	IL11	P20809	972
IL6ST	SOCS3	O14543	960
IL6ST	LIFR	P42702	960
IL6ST	OSM	P13725	945
IL6ST	JAK1	P23458	932
IL6ST	LIF	P15018	920
IL6ST	JAK2	O60674	916
IL6ST	CNTFR	P26992	906
IL6ST	STAT3	P40763	900
IL6ST	CNTF	P26441	894
IL6ST	PTPN11	Q06124	831
IL6ST	TYK2	P29597	823

IntAct

106 interactions, top by confidence:

A	B	Type	Score
IL6	IL6R	psi-mi:“MI:0915”(physical association)	0.910
IL6R	IL6	psi-mi:“MI:0914”(association)	0.910
IL6ST	IL6	psi-mi:“MI:0914”(association)	0.840
IL6ST	IL6	psi-mi:“MI:0915”(physical association)	0.840
IL6	IL6ST	psi-mi:“MI:0915”(physical association)	0.840
CNTF	CNTFR	psi-mi:“MI:0915”(physical association)	0.810
IL6ST	CNTF	psi-mi:“MI:0407”(direct interaction)	0.780
OSM	IL6ST	psi-mi:“MI:0914”(association)	0.760
OSM	IL6ST	psi-mi:“MI:0407”(direct interaction)	0.760
LIF	IL6ST	psi-mi:“MI:0407”(direct interaction)	0.740
IL6ST	LIF	psi-mi:“MI:0915”(physical association)	0.740
IL6ST	SGTB	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (117): MAGEA11 (Two-hybrid), UBQLN1 (Two-hybrid), KCNIP3 (Two-hybrid), SGTB (Two-hybrid), IL6ST (Affinity Capture-MS), IL6ST (Affinity Capture-MS), IL6ST (Biochemical Activity), TLE1 (Two-hybrid), IL6ST (Proximity Label-MS), IL6ST (Affinity Capture-MS), IL6ST (Affinity Capture-RNA), IL6ST (Affinity Capture-MS), IL6ST (Affinity Capture-Western), IL6ST (Reconstituted Complex), IL6ST (Proximity Label-MS)

ESM2 similar proteins: O02839, O08569, O19124, O62685, O62837, O88174, P01868, P01869, P04003, P05160, P06909, P08174, P08603, P08607, P14151, P14778, P15529, P16573, P20759, P20762, P36980, P40189, P49457, P59822, P79138, Q02985, Q03591, Q07968, Q28065, Q28085, Q28768, Q2VPA4, Q5R4D0, Q61475, Q61476, Q61730, Q63135, Q63514, Q63621, Q64735

Diamond homologs: B0V2N1, P14787, P40189, P40190, Q00560, Q64605, G5EF96, Q15746, Q28824, Q6PDN3, O46561, O46600, O75462, P05710, P10912, P16310, P16471, P16882, P19756, P19941, P79108, P79194, Q02092, Q04594, Q08501, Q28172, Q28235, Q28575, Q6JTA8, Q90374, Q90375, Q91094, Q91513, Q95JF2, Q95ML5, Q9JI97, Q9JM58, Q9TU69, Q9XSZ1

SIGNOR signaling

26 interactions.

A	Effect	B	Mechanism
IL6R	up-regulates	IL6ST	binding
IL6ST	up-regulates	JAK1
SOCS3	“down-regulates activity”	IL6ST	binding
IL6ST	up-regulates	JAK1	binding
LIFR	up-regulates	IL6ST	binding
IL6ST	“up-regulates activity”	JAK2	phosphorylation
IL6ST	up-regulates	SHC1	binding
IL6ST	up-regulates	ERK1/2
IL6ST	up-regulates	T_cell_activation
IL11	“up-regulates activity”	IL6ST	binding
IL6ST	“up-regulates activity”	YES1	phosphorylation
CTF1	up-regulates	IL6ST	binding
CLCF1	up-regulates	IL6ST	binding
CNTF	up-regulates	IL6ST	binding
IL11	up-regulates	IL6ST	binding
IL6	“up-regulates activity”	IL6ST	binding
LIF	up-regulates	IL6ST	binding
OSM	up-regulates	IL6ST	binding
PRKCD	up-regulates	IL6ST	phosphorylation
IL6	“up-regulates activity”	IL6ST
IL6ST	“up-regulates activity”	IL6ST	phosphorylation
PRKCD	“up-regulates activity”	IL6ST	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
IL-6-type cytokine receptor ligand interactions	6	88.5×	1e-08
Interleukin-4 and Interleukin-13 signaling	5	12.0×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor signaling pathway via STAT	6	64.8×	2e-07
cytokine-mediated signaling pathway	5	12.6×	3e-03
negative regulation of neuron apoptotic process	5	10.7×	5e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — HCC, PRAD, PROSTATE.

Clinical variants and AI predictions

ClinVar

647 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	7
Uncertain significance	380
Likely benign	200
Benign	12

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1341692	NM_002184.4(IL6ST):c.1699+4A>G	Pathogenic
1342185	NM_002184.4(IL6ST):c.560_571del (p.Ser187_Tyr190del)	Pathogenic
1342186	NM_002184.4(IL6ST):c.2277_2281dup (p.Thr761fs)	Pathogenic
1342187	NM_002184.4(IL6ST):c.2155dup (p.Ile719fs)	Pathogenic
1342189	NM_002184.4(IL6ST):c.2277T>G (p.Tyr759Ter)	Pathogenic
1929365	NM_002184.4(IL6ST):c.2199C>A (p.Cys733Ter)	Pathogenic
2030915	NM_002184.4(IL6ST):c.1485del (p.Val496fs)	Pathogenic
2127249	NM_002184.4(IL6ST):c.1824del (p.Phe608fs)	Pathogenic
2131727	NM_002184.4(IL6ST):c.1834_1835dup (p.Phe613fs)	Pathogenic
2780056	NM_002184.4(IL6ST):c.1587del (p.Lys529_Val530insTer)	Pathogenic
3728243	NM_002184.4(IL6ST):c.1002T>G (p.Tyr334Ter)	Pathogenic
4057198	NM_002184.4(IL6ST):c.1124C>G (p.Ser375Ter)	Pathogenic
4083257	NM_002184.4(IL6ST):c.2190dup (p.Ser731fs)	Pathogenic
635407	NM_002184.4(IL6ST):c.841C>T (p.Arg281Ter)	Pathogenic
638565	NM_002184.4(IL6ST):c.1210A>T (p.Asn404Tyr)	Pathogenic
638566	NM_002184.4(IL6ST):c.1493C>T (p.Pro498Leu)	Pathogenic
1013255	NM_002184.4(IL6ST):c.974-1_978del	Likely pathogenic
2029398	NM_002184.4(IL6ST):c.1699+1G>C	Likely pathogenic
3354217	NM_002184.4(IL6ST):c.491+1G>A	Likely pathogenic
3779767	NM_002184.4(IL6ST):c.2254_2258del (p.Asn752fs)	Likely pathogenic
4278482	NM_002184.4(IL6ST):c.1930C>T (p.Arg644Ter)	Likely pathogenic
4293663	NM_002184.4(IL6ST):c.772_776del (p.Asn258fs)	Likely pathogenic
4721504	NM_002184.4(IL6ST):c.658+1G>A	Likely pathogenic

SpliceAI

2583 predictions. Top by Δscore:

Variant	Effect	Δscore
5:55942664:TCTTA:T	donor_loss	1.0000
5:55942665:CTTA:C	donor_loss	1.0000
5:55942666:TTA:T	donor_loss	1.0000
5:55942667:T:TG	donor_loss	1.0000
5:55942668:A:AG	donor_loss	1.0000
5:55942668:AC:A	donor_gain	1.0000
5:55942669:CC:C	donor_gain	1.0000
5:55942747:TAATT:T	acceptor_gain	1.0000
5:55942750:TT:T	acceptor_gain	1.0000
5:55942752:C:CC	acceptor_gain	1.0000
5:55947491:A:AC	donor_gain	1.0000
5:55947492:C:CC	donor_gain	1.0000
5:55947492:CAGGT:C	donor_gain	1.0000
5:55947591:T:C	acceptor_gain	1.0000
5:55947591:T:TC	acceptor_gain	1.0000
5:55948859:TGTC:T	donor_gain	1.0000
5:55951463:CCAAA:C	donor_gain	1.0000
5:55952248:A:AC	donor_gain	1.0000
5:55952248:ACGAG:A	donor_gain	1.0000
5:55952249:C:CC	donor_gain	1.0000
5:55952249:CGAG:C	donor_gain	1.0000
5:55952249:CGAGC:C	donor_gain	1.0000
5:55956087:A:AC	donor_gain	1.0000
5:55956088:C:CC	donor_gain	1.0000
5:55956147:A:C	donor_gain	1.0000
5:55956233:TGT:T	acceptor_gain	1.0000
5:55956236:C:CC	acceptor_gain	1.0000
5:55956236:C:CG	acceptor_loss	1.0000
5:55960396:A:AC	donor_gain	1.0000
5:55960397:C:CC	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000024946 (5:55941947 A>G), RS1000219531 (5:55940338 T>C), RS1000306985 (5:55974174 G>T), RS1000310224 (5:55960161 G>C), RS1000347590 (5:55971138 C>A), RS1000365054 (5:55967685 A>G), RS1000422847 (5:55934751 T>C), RS1000446600 (5:55977237 T>C), RS1000469631 (5:55984885 G>A), RS1000474379 (5:55958604 G>A), RS1000595863 (5:55939206 G>A), RS1000611932 (5:55962151 T>C), RS1000627238 (5:55938970 C>G), RS1000696452 (5:55968959 C>G,T), RS1000725475 (5:55976296 G>C,T)

Disease associations

OMIM: gene MIM:600694 | disease phenotypes: MIM:618523, MIM:619751, MIM:619750, MIM:619752, MIM:613720, MIM:601559, MIM:146840, MIM:147060

GenCC curated gene-disease

Disease	Classification	Inheritance
hyper-IgE recurrent infection syndrome 4, autosomal recessive	Strong	Autosomal recessive
hyper-IgE recurrent infection syndrome 4A, autosomal dominant	Strong	Autosomal dominant
Stuve-Wiedemann syndrome 2	Strong	Autosomal recessive
immunodeficiency 94 with autoinflammation and dysmorphic facies	Moderate	Autosomal dominant

Mondo (7): hyper-IgE recurrent infection syndrome 4, autosomal recessive (MONDO:0032796), Stuve-Wiedemann syndrome 2 (MONDO:0030756), immunodeficiency 94 with autoinflammation and dysmorphic facies (MONDO:0030681), hyper-IgE recurrent infection syndrome 4A, autosomal dominant (MONDO:0800131), developmental and epileptic encephalopathy, 7 (MONDO:0013387), Stuve-Wiedemann syndrome (MONDO:0031280), hyper-IgE recurrent infection syndrome 1, autosomal dominant (MONDO:0007818)

Orphanet (3): KCNQ2-related developmental and epileptic encephalopathy (Orphanet:439218), Stüve-Wiedemann syndrome (Orphanet:3206), Autosomal dominant hyper-IgE syndrome due to STAT3 deficiency (Orphanet:2314)

HPO phenotypes

90 total (30 of 90 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000158	Macroglossia
HP:0000218	High palate
HP:0000256	Macrocephaly
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000403	Recurrent otitis media
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000491	Keratitis
HP:0000494	Downslanted palpebral fissures
HP:0000678	Dental crowding
HP:0000768	Pectus carinatum
HP:0000821	Hypothyroidism
HP:0000964	Eczematoid dermatitis
HP:0000998	Hypertrichosis
HP:0001047	Atopic dermatitis
HP:0001217	Clubbing
HP:0001270	Motor delay
HP:0001363	Craniosynostosis
HP:0001382	Joint hypermobility
HP:0001433	Hepatosplenomegaly
HP:0001442	Typified by somatic mosaicism
HP:0001511	Intrauterine growth retardation
HP:0001581	Recurrent skin infections
HP:0001635	Congestive heart failure
HP:0001653	Mitral regurgitation

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST001729_4	Crohn’s disease	4.000000e-12
GCST001848_128	IgG glycosylation	2.000000e-06
GCST001848_135	IgG glycosylation	2.000000e-06
GCST001848_246	IgG glycosylation	3.000000e-10
GCST001848_34	IgG glycosylation	1.000000e-10
GCST001848_354	IgG glycosylation	4.000000e-06
GCST001848_43	IgG glycosylation	1.000000e-10
GCST001848_491	IgG glycosylation	1.000000e-10
GCST001848_50	IgG glycosylation	8.000000e-06
GCST001848_529	IgG glycosylation	7.000000e-11
GCST001848_650	IgG glycosylation	2.000000e-07
GCST001848_93	IgG glycosylation	2.000000e-09
GCST006585_745	Blood protein levels	3.000000e-20
GCST90002397_34	Mean spheric corpuscular volume	5.000000e-10
GCST90013445_40	Type 1 diabetes	3.000000e-09
GCST90013445_51	Type 1 diabetes	3.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005193	serum IgG glycosylation measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C567925	Hyper-Ige Recurrent Infection Syndrome, Autosomal Dominant (supp.)
C564135	Immunodeficiency with Defective Leukocyte and Lymphocyte Function and with Response to Histamine-1 Antagonist (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3124734 (SINGLE PROTEIN), CHEMBL3137266 (PROTEIN-PROTEIN INTERACTION), CHEMBL3137274 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2228043	IL6ST		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — IL-6 receptor family

ChEMBL bioactivities

7 potent at pChembl≥5 of 9 total, top 7 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.83	IC50	1480	nM	CHEMBL3764956
5.42	Kd	3800	nM	CHEMBL4777424
5.23	IC50	5900	nM	CHEMBL3765505
5.20	IC50	6380	nM	CHEMBL3764721
5.18	IC50	6550	nM	CHEMBL3764217
5.05	IC50	9000	nM	CHEMBL3765178
5.03	IC50	9330	nM	CHEMBL3765653

PubChem BioAssay actives

7 with measured affinity, of 64 total; 7 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R,3S)-1-[3-(2-hydroxyethyl)indol-1-yl]-2-methyl-4-methylidenenonan-3-ol	1277882: Inhibition of gp130-IL6/IL-Ralpha interaction in human HepG2 cells assessed as inhibition of IL-6-induced STAT3 activation by luciferase reporter gene assay	ic50	1.4800	uM
3-[1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-5-bromoindol-3-yl]-5-[4-(trifluoromethyl)phenyl]-3,4-dihydropyrazole-2-carboxamide	1692102: Binding affinity to immobilized GP130 (unknown origin) by SPR analysis	kd	3.8000	uM
(4S)-3-[(2S,3S)-3-hydroxy-2-methyl-4-methylidenenonanoyl]-4-propan-2-yl-1,3-oxazolidin-2-one	1277882: Inhibition of gp130-IL6/IL-Ralpha interaction in human HepG2 cells assessed as inhibition of IL-6-induced STAT3 activation by luciferase reporter gene assay	ic50	5.9000	uM
(2S,3S)-3-hydroxy-1-[3-(2-hydroxyethyl)indol-1-yl]-2-methyl-4-methylidenenonan-1-one	1277882: Inhibition of gp130-IL6/IL-Ralpha interaction in human HepG2 cells assessed as inhibition of IL-6-induced STAT3 activation by luciferase reporter gene assay	ic50	6.3800	uM
(4S)-3-[(2S,3S)-4-benzyl-3-hydroxy-2-methylpent-4-enoyl]-4-propan-2-yl-1,3-oxazolidin-2-one	1277882: Inhibition of gp130-IL6/IL-Ralpha interaction in human HepG2 cells assessed as inhibition of IL-6-induced STAT3 activation by luciferase reporter gene assay	ic50	6.5500	uM
(4S)-3-[(2S,3S)-3-hydroxy-2-methyl-4-methylideneoctanoyl]-4-propan-2-yl-1,3-oxazolidin-2-one	1277882: Inhibition of gp130-IL6/IL-Ralpha interaction in human HepG2 cells assessed as inhibition of IL-6-induced STAT3 activation by luciferase reporter gene assay	ic50	9.0000	uM
(4S)-3-[(2S,3S)-3-hydroxy-2-methyl-4-methylidenedecanoyl]-4-propan-2-yl-1,3-oxazolidin-2-one	1277882: Inhibition of gp130-IL6/IL-Ralpha interaction in human HepG2 cells assessed as inhibition of IL-6-induced STAT3 activation by luciferase reporter gene assay	ic50	9.3300	uM

CTD chemical–gene interactions

96 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression, affects expression	6
sodium arsenite	increases expression, decreases reaction, increases phosphorylation, decreases expression	5
bisphenol A	decreases expression, decreases methylation, increases expression	4
Estradiol	affects expression, increases expression, affects cotreatment	4
Tetrachlorodibenzodioxin	decreases reaction, increases expression	4
Acetaminophen	affects cotreatment, increases expression, decreases expression	3
Aflatoxin B1	affects expression, decreases methylation	3
methylmercuric chloride	increases expression, decreases expression	2
N’-(7-fluoroH-pyrrolo(1,2-a)quinoxalin-4-yl)pyrazine-2-carbohydrazide	affects binding, decreases activity	2
Air Pollutants	decreases methylation, increases abundance, increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation	2
Cannabidiol	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	decreases reaction, increases phosphorylation, decreases expression	2
Tretinoin	increases expression	2
Zinc Sulfate	decreases expression, decreases reaction, increases secretion	2
Raloxifene Hydrochloride	affects binding	2
Particulate Matter	decreases methylation, increases abundance, increases expression, decreases expression	2
FR900359	affects phosphorylation	1
bisphenol F	decreases methylation	1
moringin	decreases expression	1
dicrotophos	decreases expression	1
geldanamycin	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
kojic acid	decreases expression	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1

ChEMBL screening assays

21 unique, capped per target: 21 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3131105	Binding	Binding affinity to GP130 (unknown origin) by surface plasmon resonance analysis	Drug design targeting protein-protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning: discovery of raloxifene and bazedoxifene as novel inhibitors of IL-6/GP130 interface. — J Med Chem

Cellosaurus cell lines

9 cell lines: 8 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1UH	Abcam HeLa IL6ST KO	Cancer cell line	Female
CVCL_B2NI	Abcam A-549 IL6ST KO	Cancer cell line	Male
CVCL_D7S9	Ubigene A-549 IL6ST KO	Cancer cell line	Male
CVCL_D8N9	Ubigene HCT 116 IL6ST KO	Cancer cell line	Male
CVCL_D9H6	Ubigene HEK293 IL6ST KO	Transformed cell line	Female
CVCL_E0F6	Ubigene HeLa IL6ST KO	Cancer cell line	Female
CVCL_E0ZJ	Ubigene NCI-H1299 IL6ST KO	Cancer cell line	Male
CVCL_SS48	HAP1 IL6ST (-) 1	Cancer cell line	Male
CVCL_SS49	HAP1 IL6ST (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

8 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00033982	PHASE3	COMPLETED	Posaconazole to Treat Invasive Fungal Infections
NCT00527878	PHASE2	TERMINATED	Effect of Ranitidine on Hyper-IgE Recurrent Infection (Job’s) Syndrome
NCT02996448	PHASE2	TERMINATED	Safety, Tolerability, and Immunogenicity of One Dose of NDV 3A Vaccine in People With STAT3-Mutated Hyper-IgE Syndrome
NCT00001515	PHASE1	COMPLETED	Diagnostic Effectiveness of Virtual Bronchoscopy
NCT00260702	PHASE1	COMPLETED	Omalizumab to Treat Hyper-IgE (Job’s) Syndrome
NCT00005933	Not specified	COMPLETED	Learning and Behavior Problems in Children With Chronic Granulomatous Disease and Related Disorders
NCT00006150	Not specified	RECRUITING	Natural History, Management, and Genetics of the Hyperimmunoglobulin E Recurrent Infection Syndrome (HIES)
NCT02228941	Not specified	UNKNOWN	NFIL3-induced Pathological Enhancement of IgE Class Switch Recombination in Hyper-IgE Syndrome