IL6R

Summary

IL6R (interleukin 6 receptor, HGNC:6019) is a protein-coding gene on chromosome 1q21.3, encoding Interleukin-6 receptor subunit alpha (P08887). Part of the receptor for interleukin 6.

This gene encodes a subunit of the interleukin 6 (IL6) receptor complex. Interleukin 6 is a potent pleiotropic cytokine that regulates cell growth and differentiation and plays an important role in the immune response. The IL6 receptor is a protein complex consisting of this protein and interleukin 6 signal transducer (IL6ST/GP130/IL6-beta), a receptor subunit also shared by many other cytokines. Dysregulated production of IL6 and this receptor are implicated in the pathogenesis of many diseases, such as multiple myeloma, autoimmune diseases and prostate cancer. Alternatively spliced transcript variants encoding distinct isoforms have been identified in this gene. A pseudogene of this gene is found on chromosome 9.

Source: NCBI Gene 3570 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyper-IgE recurrent infection syndrome 5, autosomal recessive (Strong, GenCC)
• GWAS associations: 79
• Clinical variants (ClinVar): 345 total — 1 pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• MANE Select transcript: NM_000565

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6019
Approved symbol	IL6R
Name	interleukin 6 receptor
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	CD126, IL-6R, IL-1Ra, IL6RA, gp80
Ensembl gene	ENSG00000160712
Ensembl biotype	protein_coding
OMIM	147880
Entrez	3570

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 15 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000344086, ENST00000368485, ENST00000476006, ENST00000502679, ENST00000507256, ENST00000512471, ENST00000515190, ENST00000622330, ENST00000858505, ENST00000858506, ENST00000858507, ENST00000858508, ENST00000858509, ENST00000858510, ENST00000858511, ENST00000858512, ENST00000954333

RefSeq mRNA: 9 — MANE Select: NM_000565 NM_000565, NM_001206866, NM_001382769, NM_001382770, NM_001382771, NM_001382772, NM_001382773, NM_001382774, NM_181359

CCDS: CCDS1067, CCDS1068, CCDS72927

Canonical transcript exons

ENST00000368485 — 10 exons

Exon	Start	End
ENSE00001174398	154435969	154436110
ENSE00001174403	154434990	154435156
ENSE00001174408	154434519	154434700
ENSE00001174416	154430483	154430606
ENSE00001174424	154429196	154429444
ENSE00001796755	154465134	154469450
ENSE00003557564	154454488	154454581
ENSE00003630319	154449911	154449980
ENSE00003646716	154448125	154448171
ENSE00003841365	154405343	154405714

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 96.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.1123 / max 522.5075, expressed in 1388 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5502	6.6151	1074
5504	6.2754	804
5503	2.0467	417
5501	1.3858	422
5499	0.3572	101
5500	0.1659	71
5505	0.1103	43
5498	0.1077	54
5512	0.0329	10
5514	0.0153	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	96.23	gold quality
monocyte	CL:0000576	94.93	gold quality
leukocyte	CL:0000738	94.62	gold quality
mononuclear cell	CL:0000842	94.54	gold quality
right lobe of liver	UBERON:0001114	93.96	gold quality
gastrocnemius	UBERON:0001388	93.85	gold quality
liver	UBERON:0002107	92.87	gold quality
granulocyte	CL:0000094	92.50	gold quality
muscle of leg	UBERON:0001383	92.09	gold quality
trabecular bone tissue	UBERON:0002483	91.84	gold quality
bone marrow cell	CL:0002092	91.32	gold quality
synovial joint	UBERON:0002217	91.01	gold quality
bone marrow	UBERON:0002371	90.57	gold quality
saphenous vein	UBERON:0007318	90.55	gold quality
mucosa of stomach	UBERON:0001199	89.73	gold quality
cartilage tissue	UBERON:0002418	89.69	gold quality
superficial temporal artery	UBERON:0001614	88.83	gold quality
duodenum	UBERON:0002114	88.81	gold quality
lymph node	UBERON:0000029	88.75	gold quality
body of tongue	UBERON:0011876	88.54	gold quality
superior surface of tongue	UBERON:0007371	88.51	gold quality
colonic mucosa	UBERON:0000317	88.37	gold quality
tongue	UBERON:0001723	88.28	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.12	gold quality
jejunum	UBERON:0002115	88.03	gold quality
muscle organ	UBERON:0001630	87.74	gold quality
lower lobe of lung	UBERON:0008949	87.73	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.59	gold quality
vermiform appendix	UBERON:0001154	86.77	gold quality
inferior vagus X ganglion	UBERON:0005363	86.71	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	19.59
E-CURD-112	yes	14.37
E-MTAB-9067	yes	12.63
E-GEOD-100618	no	158.69

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F3, PPARA, SMAD2, TP53, TWIST1

miRNA regulators (miRDB)

129 targeting IL6R, 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-513A-5P	100.00	69.77	2465
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-629-3P	99.85	67.99	1875

Literature-anchored findings (GeneRIF, showing 40)

• Shedding of the interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts. (PMID:11884403)
• Serum sIL-6R levels reflect proliferative kinetics of the progenitors after stimulation by chemotherapy plus granulocyte colony-stimulating factor. (PMID:12002769)
• the soluble interleukin-6 receptor isoform induces major changes in gene expression profile of human hepatoma cells (PMID:12008038)
• Proteolysis of interleukin-6 receptor (IL-6R) by Porphyromonas gingivalis cysteine proteinases (gingipains) inhibits interleukin-6-mediated cell activation. (PMID:12079407)
• Human bone marrow-derived mesenchymal cells do not differentiate into the osteogenic lineage until Gp130 is activated by soluble interleukin-6 receptors and interleukin-6. (PMID:12372336)
• combined measurements of serum interleukin-6 soluble receptor and interleukin-6 may be helpful in identifying patients with untreated hyperparathyroidism who are more likely to experience bone loss at the total femur (PMID:12414855)
• results show for the first time that interleukin-6 (IL), in the presence of its soluble receptor (sIL-6R), induces activation of JAK1, JAK2, and STAT1/STAT3 proteins in bovine articular chondrocytes (PMID:12419823)
• soluble proteins of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-6 receptor subunit gp80 (sIL-6R gp80), as markers of multiple sclerosis (PMID:12445803)
• X-ray structure (2.4 A) of the IL-6R ectodomains shows the N-terminal strand of the D(1)domain is disulfide-bonded to domain D(2). The head-to-tail packing of 2 closely associated IL-6R molecules may be the configuration of the physiological IL-6R dimer. (PMID:12461182)
• There is no significant effect of IL-18 on the release of both soluble receptors of IL-6. (PMID:12472176)
• Induction of VEGF seems to be regulated by the extent of the IL-6 receptor expression on pancreatic cancer cells. (PMID:12553038)
• only in a subset of both benign and malignant thyroid nodules the interleukin-6/interleukin-6 receptor signal could be induced by the CD30 ligand/CD30 (PMID:12553555)
• IL-6r and TNF-alpha increase in parallel to VEGF and FGF-2 with increasing stage of multiple myeloma. (PMID:12574959)
• identification of existence as a preformed dimer in plasma membrane (PMID:12633863)
• IL-6 receptor binds to CTNF and is involved in neuroprotection (PMID:12643274)
• type 1 tumor necrosis factor receptor shedding aminopeptidase regulator(ARTS-1) promotes shedding of two cytokine receptor superfamilies, type I cytokine receptor superfamily (interleukin-6Ralpha) and tumor necrosis factor receptor superfamily (TNFR1) (PMID:12748171)
• might also be valuable biochemical marker in the evaluation of oocyte maturation (PMID:12748876)
• IL-6 derived from blood during breakdown of blood-retinal barrier and produced by retinal pigment epithelial(RPE) cells and hematogenous soluble interleukin-6 receptor cause RPE proliferation. (PMID:12789531)
• 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)
• cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (PMID:12832423)
• IL-15 alone, similarly to IL-18, has no significant ability for regulation of both soluble IL-6 receptors, sIL-6R and sgp130, released by human neutrophils. (PMID:12857602)
• IL-6R alpha and IGF-I receptors exist on the plasma membrane in close proximity, facilitating the efficient assembly of 2 receptors in response to IL-6 in myeloma (PMID:14592826)
• In prostatectomy patients, preoperative plasma levels of TGF-beta(1) and IL-6sR are associated with metastases to regional lymph nodes and disease progression. (PMID:15041717)
• Serum pro-inflammatory cytokine IL-6 or TNF-alpha concentrations were neither increased in subjects with impaired glucose tolerance nor closely correlated with the components of the metabolic syndrome. (PMID:15063602)
• Study using normal peritoneal mesothelial cells and inflammatory exudates reveals the comparable ability of two types of soluble IL-6 receptor isoforms to regulate neutrophil recruitment. (PMID:15100312)
• IL-6 and sIL-6R may contribute to the pathogenesis of endometriosis-associated infertility (PMID:15166129)
• NMR structure of the carboxyl terminal domain of the cytokine binding module of the interleukin-6 receptor (PMID:15213442)
• Butyrate acts by inhibiting IL-6-induced interleukin 6 receptor expression in colorectal carcinoma cells. (PMID:15284182)
• Detailed pathway analysis revealed that BM stromal cells stimulate STAT3 via the IL-6R, and MEK1/ERK1 pathways, via IL-6R-independent mechanisms (PMID:15297310)
• Data describe the relationship between interleukin-6 and interleukin-6 soluble receptor in stroke patients. (PMID:15456942)
• Asp358Ala polymorphism of the IL6R associates with type 2 diabetes in Danish whites. (PMID:15561970)
• Variants are associated with Type II diabetes and diabetic nephropathy. (PMID:15562008)
• the soluble form of IL-6 receptor is expressed on normal human platelets (PMID:15579373)
• Serum sIL-6R levels is a predictive factor for responsiveness to chemotherapy and an indicator of disease activity. (PMID:15625895)
• IL-1beta- and TNFalpha-mediated induction of IL-6R shedding in osteoblast-like cells is at least partly dependent on tumor necrosis factor alpha-converting enzyme activation. (PMID:15641051)
• co-expression of IL-6 and its specific receptor (IL-6Ralpha) in keloid fibroblasts that points to the existence of an IL-6 autocrine loop in these cells. (PMID:15816827)
• 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)
• Airway epithelial cell IL-6 and soluble IL-6 receptor alpha participate in inflammatory trans-signaling in response to bacterial pathogens. (PMID:16034137)
• Production of IL-6 and its soluble receptors by stimulated peripheral blood monocytes appears to be inversely correlated with serum cholesterol levels in hemodialysis patients. (PMID:16127269)
• CD30-L/CD30 and IL-6/IL-6R systems could play a major role in the pathogenesis of Graves’disease (GD), but the expression of CD30L/CD30 and IL-6/IL-6R in Hashimoto’s thyroiditis (HT) suggests that Th2 mechanisms are involved in tissue damage. (PMID:16372246)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	ghrb	ENSDARG00000007671
danio_rerio	il11ra	ENSDARG00000026736
danio_rerio	lifrb	ENSDARG00000039863
danio_rerio	ghra	ENSDARG00000054771
danio_rerio	lifra	ENSDARG00000098857
danio_rerio	il6r	ENSDARG00000104474
mus_musculus	Il6ra	ENSMUSG00000027947
rattus_norvegicus	Il6r	ENSRNOG00000020811

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), IL6ST (ENSG00000134352), IL11RA (ENSG00000137070), OSMR (ENSG00000145623), IL2RG (ENSG00000147168), IL23R (ENSG00000162594), IL31RA (ENSG00000164509), IL3RA (ENSG00000185291), CSF2RA (ENSG00000198223), CRLF2 (ENSG00000205755)

Protein

Protein identifiers

Interleukin-6 receptor subunit alpha — P08887 (reviewed: P08887)

Alternative names: IL-6R 1, Membrane glycoprotein 80

All UniProt accessions (6): P08887, A0A087WTB5, A0N0L5, D6R9R8, H0Y949, H0Y9B1

UniProt curated annotations — full annotation on UniProt →

Function. Part of the receptor for interleukin 6. Binds to IL6 with low affinity, but does not transduce a signal. Signal activation necessitate an association with IL6ST. Activation leads to the regulation of the immune response, acute-phase reactions and hematopoiesis. The interaction with membrane-bound IL6R and IL6ST stimulates ‘classic signaling’, the restricted expression of the IL6R limits classic IL6 signaling to only a few tissues such as the liver and some cells of the immune system. Whereas the binding of IL6 and soluble IL6R to IL6ST stimulates ’trans-signaling’. Alternatively, ‘cluster signaling’ occurs when membrane-bound IL6:IL6R complexes on transmitter cells activate IL6ST receptors on neighboring receiver cells. Signaling via the membrane-bound IL6R is mostly regenerative and anti-inflammatory. Drives naive CD4(+) T cells to the Th17 lineage, through ‘cluster signaling’ by dendritic cells. Soluble form of IL6 receptor (sIL6R) that acts as an agonist of IL6 activity. The IL6:sIL6R complex (hyper-IL6) binds to IL6ST/gp130 on cell surfaces and induces signaling also on cells that do not express membrane-bound IL6R in a process called IL6 ’trans-signaling’. sIL6R is causative for the pro-inflammatory properties of IL6 and an important player in the development of chronic inflammatory diseases. In complex with IL6, is required for induction of VEGF production. Plays a protective role during liver injury, being required for maintenance of tissue regeneration. ‘Trans-signaling’ in central nervous system regulates energy and glucose homeostasis. Soluble form of IL6 receptor (sIL6R) that acts as an agonist of IL6 activity. The IL6:sIL6R complex (hyper-IL6) binds to IL6ST/gp130 on cell surfaces and induces signaling also on cells that do not express membrane-bound IL6R in a process called IL6 ’trans-signaling’. sIL6R is causative for the pro-inflammatory properties of IL6 and an important player in the development of chronic inflammatory diseases. In complex with IL6, is required for induction of VEGF production. Plays a protective role during liver injury, being required for maintenance of tissue regeneration. ‘Trans-signaling’ in central nervous system regulates energy and glucose homeostasis.

Subunit / interactions. Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; first binds to IL6 to associate with the signaling subunit IL6ST. Interacts (via N-terminal ectodomain) with SORL1; this interaction may affect IL6-binding to IL6R, hence decrease IL6 ‘classic-signaling’. Also interacts with SORL1; this interaction leads to soluble IL6R internalization. May form a trimeric complex with the soluble SORL1 ectodomain and circulating IL6 receptor; this interaction might stabilize circulating IL6, hence promote IL6 ’trans-signaling,. Also interacts with SORL1; this interaction leads to soluble IL6R internalization. May form a trimeric complex with the soluble SORL1 ectodomain and circulating IL6 receptor; this interaction might stabilize circulating IL6, hence promote IL6 ’trans-signaling,.

Subcellular location. Cell membrane Secreted Secreted.

Tissue specificity. Expressed in peripheral blood mononuclear cells and weakly found in urine and serum. 1%-20% of the total sIL6R in plasma is generated by alternative splicing.

Post-translational modifications. A short soluble form is released from the membrane by proteolysis. The sIL6R is formed mostly by limited proteolysis of membrane-bound receptors, a process referred to as ectodomain shedding, but is also directly secreted from the cells after alternative mRNA splicing. mIL6R is cleaved by the proteases ADAM10 and ADAM17. Glycosylated. Glycosylation is dispensable for transport, signaling, and cell-surface turnover. Glycosylation at Asn-55 is a protease-regulatory exosite. Glycosylation is required for ADAM17-mediated proteolysis.

Disease relevance. Hyper-IgE syndrome 5, autosomal recessive, with recurrent infections (HIES5) [MIM:618944] An immunologic disorder characterized by recurrent sinopulmonary and deep skin infections, mostly caused by bacteria, including H.influenza and S.aureus. Additional features include asthma, atopic dermatitis, and impaired inflammatory responses during infection. Disease onset is in early infancy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Classic and trans-signaling are both inhibited by tocilizumab, a humanized monoclonal antibody that blocks interleukin IL6R signaling.

Domain organisation. The two fibronectin type-III-like domains, contained in the N-terminal part, form together a cytokine-binding domain. The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.

Polymorphism. Genetic variations in IL6R determine soluble IL6R serum levels [MIM:614689]. Genetic variations in IL6R define the IL6 serum level quantitative trait locus [MIM:614752].

Similarity. Belongs to the type I cytokine receptor family. Type 3 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P08887-1	1, Long, mIL6R	yes
P08887-2	2, Short, sIL6R

RefSeq proteins (9): NP_000556, NP_001193795, NP_001369698, NP_001369699, NP_001369700, NP_001369701, NP_001369702, NP_001369703, NP_852004 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003530	Hematopoietin_rcpt_L_F3_CS	Conserved_site
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR007110	Ig-like_dom	Domain
IPR013151	Immunoglobulin_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015321	TypeI_recpt_CBD	Domain
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF00047, PF09240

UniProt features (97 total): mutagenesis site 35, strand 23, glycosylation site 6, disulfide bond 4, sequence variant 4, compositionally biased region 3, domain 3, turn 3, chain 2, region of interest 2, site 2, splice variant 2, topological domain 2, helix 2, signal peptide 1, short sequence motif 1, transmembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
1N26	X-RAY DIFFRACTION	2.4
5FUC	X-RAY DIFFRACTION	2.7
7DC8	X-RAY DIFFRACTION	2.76
8QY5	ELECTRON MICROSCOPY	3.1
8QY6	ELECTRON MICROSCOPY	3.16
8IOW	ELECTRON MICROSCOPY	3.2
8D82	ELECTRON MICROSCOPY	3.22
8J6F	ELECTRON MICROSCOPY	3.3
1P9M	X-RAY DIFFRACTION	3.65
2ARW	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08887-F1	78.65	0.56

Antibody-complex structures (SAbDab): 4 — 5FUC, 7DC8, 8IOW, 8J6F

Functional residue map

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

Catalytic / active sites (2): 245 (not glycosylated); 355–356 (cleavage; by adam10 and adam17)

Disulfide bonds (4): 25–193, 47–96, 121–132, 165–176

Glycosylation sites (6): 55, 93, 221, 245, 350, 352

Mutagenesis-validated functional residues (35):

Position	Phenotype
55	strongly induces cleavage and sil6r levels. no effect on il6r signaling; when associated with a-93, a-221, a-245 and a-3
57	strongly induces cleavage and sil6r levels.
93	no effect on cleavage or sil6r levels. no effect on il6r signaling; when associated with a-55, a-221, a-245 and a-350. l
121	complete loss of ligand-binding.
122	no change of ligand-binding and il6 signaling.
132	complete loss of ligand-binding.
134	complete loss of ligand-binding.
140	no change of ligand-binding and il6 signaling.
153	no change of ligand-binding and il6 signaling.
165	complete loss of ligand-binding.
174	no change of ligand-binding and il6 signaling.
176	complete loss of ligand-binding.
184	30% decrease of ligand-binding and il6 signaling.
190	80% decrease of ligand-binding and no il6 signaling.
193	complete loss of ligand-binding.
211	no change of ligand-binding and il6 signaling.
217	complete loss of ligand-binding.
221	no effect on cleavage or sil6r levels. no effect on il6r signaling; when associated with a-55, a-93, a-245 and a-350. lo
232	30% decrease of ligand-binding and il6 signaling.
233	30% decrease of ligand-binding and increase of il6 signaling.
245	slightly induces cleavage and sil6r levels. no effect on il6r signaling; when associated with a-55, a-93, a-221 and a-35
254	50% decrease of ligand-binding and il6 signaling.
277	30% increase of ligand-binding and 100% increase in il6 signaling.
278	50% decrease of ligand-binding and 50% increase in il6 signaling.
279	complete loss of ligand-binding.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1059683	Interleukin-6 signaling
R-HSA-110056	MAPK3 (ERK1) activation
R-HSA-112411	MAPK1 (ERK2) activation
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-9616222	Transcriptional regulation of granulopoiesis
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-9958825	Activation of STAT3 by cadherin engagement

MSigDB gene sets: 623 (showing top): PID_SHP2_PATHWAY, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_6HR_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_INTERLEUKIN_6_SIGNALING, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, LOPEZ_MESOTHELIOMA_SURVIVAL_OVERALL_UP, GOBP_PLATELET_ACTIVATION, MODULE_64, GOBP_INSULIN_SECRETION

GO Biological Process (28): hepatic immune response (GO:0002384), neutrophil mediated immunity (GO:0002446), monocyte chemotaxis (GO:0002548), positive regulation of leukocyte chemotaxis (GO:0002690), acute-phase response (GO:0006953), positive regulation of cell population proliferation (GO:0008284), vascular endothelial growth factor production (GO:0010573), cytokine-mediated signaling pathway (GO:0019221), endocrine pancreas development (GO:0031018), negative regulation of interleukin-8 production (GO:0032717), positive regulation of chemokine production (GO:0032722), positive regulation of interleukin-6 production (GO:0032755), negative regulation of collagen biosynthetic process (GO:0032966), response to cytokine (GO:0034097), positive regulation of MAPK cascade (GO:0043410), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of smooth muscle cell proliferation (GO:0048661), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830), interleukin-6-mediated signaling pathway (GO:0070102), ciliary neurotrophic factor-mediated signaling pathway (GO:0070120), positive regulation of glomerular mesangial cell proliferation (GO:0072126), T-helper 17 cell lineage commitment (GO:0072540), extrinsic apoptotic signaling pathway (GO:0097191), cell surface receptor signaling pathway via STAT (GO:0097696), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), developmental process (GO:0032502), interleukin-11-mediated signaling pathway (GO:0038154)

GO Molecular Function (11): cytokine receptor activity (GO:0004896), interleukin-6 receptor activity (GO:0004915), interleukin-11 receptor activity (GO:0004921), enzyme binding (GO:0019899), interleukin-11 binding (GO:0019970), interleukin-6 binding (GO:0019981), protein homodimerization activity (GO:0042803), ciliary neurotrophic factor binding (GO:0070119), ciliary neurotrophic factor receptor activity (GO:0004897), interleukin-6 receptor binding (GO:0005138), protein binding (GO:0005515)

GO Cellular Component (9): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), interleukin-6 receptor complex (GO:0005896), external side of plasma membrane (GO:0009897), apical plasma membrane (GO:0016324), signaling receptor complex (GO:0043235), ciliary neurotrophic factor receptor complex (GO:0070110), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
RAF-independent MAPK1/3 activation	2
Interleukin-6 family signaling	1
Signaling by Interleukins	1
Developmental Biology	1
SARS-CoV Infections	1
Adherens junctions interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine binding	4
cytokine receptor activity	3
leukocyte chemotaxis	2
positive regulation of cytokine production	2
defense response to bacterium	2
cytokine-mediated signaling pathway	2
growth factor binding	2
cellular anatomical structure	2
plasma membrane signaling receptor complex	2
organ or tissue specific immune response	1
myeloid leukocyte mediated immunity	1
mononuclear cell migration	1
myeloid leukocyte migration	1
positive regulation of leukocyte migration	1
regulation of leukocyte chemotaxis	1
positive regulation of chemotaxis	1
acute inflammatory response	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
cytokine production	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
pancreas development	1
endocrine system development	1
anatomical structure development	1
negative regulation of cytokine production	1
interleukin-8 production	1
regulation of interleukin-8 production	1
chemokine production	1
regulation of chemokine production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
negative regulation of biosynthetic process	1
negative regulation of collagen metabolic process	1
collagen biosynthetic process	1
regulation of collagen biosynthetic process	1
response to peptide	1
MAPK cascade	1
regulation of MAPK cascade	1

Protein interactions and networks

STRING

2716 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL6R	IL6	P05231	999
IL6R	IL6ST	P40189	988
IL6R	IL11	P20809	983
IL6R	TNF	P01375	977
IL6R	IL1B	P01584	974
IL6R	TNFRSF1A	P19438	914
IL6R	STAT3	P40763	903
IL6R	TYK2	P29597	893
IL6R	IL27RA	Q6UWB1	889
IL6R	CNTF	P26441	884
IL6R	IL11RA	Q14626	883
IL6R	SOCS3	O14543	869
IL6R	IL1A	P01583	821
IL6R	IL1R1	P14778	820
IL6R	IL4R	P24394	817

IntAct

49 interactions, top by confidence:

A	B	Type	Score
IL6	IL6R	psi-mi:“MI:0915”(physical association)	0.910
IL6R	IL6	psi-mi:“MI:0407”(direct interaction)	0.910
IL6R	IL6	psi-mi:“MI:0915”(physical association)	0.910
IL6R	IL6	psi-mi:“MI:0914”(association)	0.910
IL6R	SORL1	psi-mi:“MI:0407”(direct interaction)	0.620
SORL1	IL6R	psi-mi:“MI:0915”(physical association)	0.620
SORL1	IL6R	psi-mi:“MI:0403”(colocalization)	0.620
K2	IL6R	psi-mi:“MI:0407”(direct interaction)	0.590
IL6R	K2	psi-mi:“MI:0915”(physical association)	0.590
SORL1	IL6	psi-mi:“MI:0915”(physical association)	0.570
IL6R	SGTB	psi-mi:“MI:0915”(physical association)	0.560
CD248	IL6R	psi-mi:“MI:0407”(direct interaction)	0.560
IL6R	ISLR2	psi-mi:“MI:0915”(physical association)	0.540
ISLR2	IL6R	psi-mi:“MI:0407”(direct interaction)	0.540
ICAM5	IL6R	psi-mi:“MI:0407”(direct interaction)	0.440
WFIKKN2	IL6R	psi-mi:“MI:0407”(direct interaction)	0.440
IL6R	LTF	psi-mi:“MI:0407”(direct interaction)	0.440
IL6R	IGFBPL1	psi-mi:“MI:0407”(direct interaction)	0.440
IL6R	IGFBP7	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (40): TBCK (Affinity Capture-MS), PPP1R21 (Affinity Capture-MS), MID1 (Affinity Capture-MS), C12orf4 (Affinity Capture-MS), CRYZL1 (Affinity Capture-MS), FANCB (Affinity Capture-MS), FANCL (Affinity Capture-MS), C17orf70 (Affinity Capture-MS), CETN2 (Affinity Capture-MS), COPRS (Affinity Capture-MS), IL6R (Affinity Capture-RNA), IL6R (Reconstituted Complex), IL6 (Reconstituted Complex), CNTF (Reconstituted Complex), CNTF (Affinity Capture-Western)

ESM2 similar proteins: A5D8T8, O35217, O75078, O75882, O75900, O88272, O88507, O88676, O95633, P08887, P0C7M8, P0C7M9, P26992, P78539, Q00961, Q01098, Q08406, Q0ZCA7, Q14957, Q1LZB9, Q2TBM7, Q4V7F2, Q5EA46, Q5VV63, Q63769, Q642A6, Q6A051, Q6IA17, Q6P1D5, Q6PCB0, Q6UXF7, Q71DR4, Q7TNS7, Q7TSQ1, Q8NCF0, Q8R2Z5, Q8R366, Q91XD7, Q96FT7, Q96HD1

Diamond homologs: O18796, O88507, P08887, P22272, P22273, P26992, P51641, Q08406, Q71DR4, O35228, Q14213, Q14626, Q5RF19, P70225, Q64385, Q99MF4, D3YYU8

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
IL6R	up-regulates	IL6ST	binding
IL6	up-regulates	IL6R	binding
IL6R	“up-regulates activity”	JAK2	phosphorylation
IL6	“up-regulates activity”	IL6R	binding
Tocilizumab	“down-regulates activity”	IL6R	binding
hsa-miR-451a	“down-regulates quantity by repression”	IL6R	“post transcriptional regulation”
TFEB	“up-regulates quantity by expression”	IL6R	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	143
Likely benign	160
Benign	22

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3609111	NM_000565.4(IL6R):c.494G>C (p.Cys165Ser)	Pathogenic

SpliceAI

2180 predictions. Top by Δscore:

Variant	Effect	Δscore
1:154430481:A:AG	acceptor_gain	1.0000
1:154430482:G:GA	acceptor_gain	1.0000
1:154430601:G:GT	donor_gain	1.0000
1:154430603:AGTT:A	donor_gain	1.0000
1:154430604:GTT:G	donor_gain	1.0000
1:154430604:GTTG:G	donor_gain	1.0000
1:154430605:TTGT:T	donor_gain	1.0000
1:154430607:G:GG	donor_gain	1.0000
1:154434517:A:AG	acceptor_gain	1.0000
1:154434518:G:GA	acceptor_gain	1.0000
1:154434648:T:TA	donor_gain	1.0000
1:154434649:A:AA	donor_gain	1.0000
1:154434664:T:G	donor_gain	1.0000
1:154434689:G:T	donor_gain	1.0000
1:154434701:G:GG	donor_gain	1.0000
1:154434705:G:GG	donor_gain	1.0000
1:154448120:CGCA:C	acceptor_loss	1.0000
1:154448121:GCA:G	acceptor_loss	1.0000
1:154448123:A:AG	acceptor_gain	1.0000
1:154448123:A:C	acceptor_loss	1.0000
1:154448124:G:GG	acceptor_gain	1.0000
1:154448124:GA:G	acceptor_gain	1.0000
1:154405398:G:GT	donor_gain	0.9900
1:154405398:G:T	donor_gain	0.9900
1:154405713:GG:G	donor_gain	0.9900
1:154405714:GG:G	donor_gain	0.9900
1:154429194:A:AG	acceptor_gain	0.9900
1:154429195:G:GG	acceptor_gain	0.9900
1:154429195:GA:G	acceptor_gain	0.9900
1:154429195:GAGGT:G	acceptor_gain	0.9900

AlphaMissense

3040 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:154436079:G:C	W306C	0.998
1:154436079:G:T	W306C	0.998
1:154435056:T:A	V236D	0.996
1:154435081:G:C	W244C	0.996
1:154435081:G:T	W244C	0.996
1:154435106:T:C	F253L	0.996
1:154435108:T:A	F253L	0.996
1:154435108:T:G	F253L	0.996
1:154436077:T:A	W306R	0.996
1:154436077:T:C	W306R	0.996
1:154435122:G:C	R258P	0.995
1:154436080:A:C	S307R	0.995
1:154436082:C:A	S307R	0.995
1:154436082:C:G	S307R	0.995
1:154435050:T:C	L234P	0.994
1:154435061:T:A	W238R	0.994
1:154435061:T:C	W238R	0.994
1:154435997:T:C	I279T	0.994
1:154436039:G:C	R293P	0.994
1:154436070:G:C	W303C	0.994
1:154436070:G:T	W303C	0.994
1:154435063:G:C	W238C	0.993
1:154435063:G:T	W238C	0.993
1:154436033:A:C	Q291P	0.993
1:154436071:A:C	S304R	0.993
1:154436073:C:A	S304R	0.993
1:154436073:C:G	S304R	0.993
1:154435005:C:A	P219H	0.992
1:154435079:T:A	W244R	0.992
1:154435079:T:C	W244R	0.992

dbSNP variants (sampled 300 via entrez): RS1000001560 (1:154452623 A>G), RS1000216346 (1:154425079 A>G), RS1000244757 (1:154464675 C>T), RS1000247425 (1:154425380 G>A), RS1000281141 (1:154405538 C>A), RS1000294795 (1:154422438 A>G), RS1000385580 (1:154451300 C>G), RS1000413125 (1:154430775 T>A,C,G), RS1000442014 (1:154457943 TTTTTTCTTTTTC>T,TTTTTTC,TTTTTTCTTTTTCTTTTTC,TTTTTTCTTTTTCTTTTTCTTTTTC), RS1000494457 (1:154421502 G>A,C,T), RS1000545915 (1:154423635 G>A), RS1000580078 (1:154424104 C>G,T), RS1000631675 (1:154463472 C>T), RS1000635525 (1:154469783 A>G), RS1000697219 (1:154429716 G>T)

Disease associations

OMIM: gene MIM:147880 | disease phenotypes: MIM:618944

GenCC curated gene-disease

Disease	Classification	Inheritance
hyper-IgE recurrent infection syndrome 5, autosomal recessive	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hyper-IgE recurrent infection syndrome 5, autosomal recessive	Limited	AR

Mondo (1): hyper-IgE recurrent infection syndrome 5, autosomal recessive (MONDO:0030069)

Orphanet (0):

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0001047	Atopic dermatitis
HP:0001581	Recurrent skin infections
HP:0002788	Recurrent upper respiratory tract infections
HP:0002850	Decreased circulating total IgM
HP:0003212	Increased circulating IgE concentration
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0030388	Decreased class-switched memory B cell proportion
HP:0030783	Increased circulating interleukin 6 concentration
HP:0031292	Cutaneous abscess
HP:0032437	Reduced circulating C-reactive protein concecntration
HP:0033104	Inappropriate absence of fever
HP:0100658	Cellulitis

GWAS associations

79 associations (top):

Study	Trait	p-value
GCST000106_5	Pulmonary function	7.000000e-06
GCST000178_1	C-reactive protein	2.000000e-08
GCST000189_24	Protein quantitative trait loci	2.000000e-57
GCST000368_2	Fibrinogen	2.000000e-11
GCST000430_1	C-reactive protein	2.000000e-14
GCST000965_9	C-reactive protein levels	2.000000e-48
GCST001226_3	Asthma	2.000000e-08
GCST002147_12	Fibrinogen	6.000000e-27
GCST002318_156	Rheumatoid arthritis	4.000000e-09
GCST002318_180	Rheumatoid arthritis	5.000000e-06
GCST002365_13	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 2 peripheral neuropathy)	5.000000e-06
GCST002665_2	Cerebrospinal fluid levels of Alzheimer’s disease-related proteins	6.000000e-63
GCST003116_35	Coronary artery disease	3.000000e-09
GCST003117_8	Myocardial infarction	1.000000e-07
GCST003184_29	Atopic dermatitis	5.000000e-10
GCST003194_10	Fibrinogen levels	3.000000e-36
GCST003877_2	Abdominal aortic aneurysm	5.000000e-13
GCST004121_14	Fibrinogen levels	2.000000e-28
GCST004122_32	Fibrinogen levels	9.000000e-29
GCST004609_185	Monocyte percentage of white cells	9.000000e-10
GCST004787_42	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	2.000000e-09
GCST004861_30	Itch intensity from mosquito bite	9.000000e-09
GCST004863_42	Mosquito bite size	2.000000e-07
GCST004865_48	Itch intensity from mosquito bite adjusted by bite size	4.000000e-06
GCST005038_35	Allergic disease (asthma, hay fever or eczema)	4.000000e-13
GCST005194_175	Coronary artery disease	3.000000e-11
GCST005195_50	Coronary artery disease	7.000000e-15
GCST005196_189	Coronary artery disease	6.000000e-16
GCST005528_21	Juvenile idiopathic arthritis (oligoarticular or rheumatoid factor-negative polyarticular)	1.000000e-08
GCST005529_44	Ankylosing spondylitis	3.000000e-13

EFO canonical traits (18, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004458	C-reactive protein measurement
EFO:0004814	interleukin-6 receptor measurement
EFO:0000180	HIV-1 infection
EFO:0004810	interleukin-6 measurement
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0007989	monocyte percentage of leukocytes
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0005128	albumin:globulin ratio measurement
EFO:0007796	parental longevity
EFO:0004747	protein measurement
EFO:0008187	interleukin 6 receptor subunit alpha measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0005091	monocyte count
EFO:0004309	platelet count
EFO:0009188	Red cell distribution width
EFO:0004533	alkaline phosphatase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2364155 (SINGLE PROTEIN), CHEMBL3137266 (PROTEIN-PROTEIN INTERACTION)

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11265618	Efficacy	3	tocilizumab	Rheumatoid arthritis
rs12083537	Efficacy	3	tocilizumab	Rheumatoid arthritis
rs4329505	Efficacy	4	tocilizumab	Rheumatoid arthritis

PharmGKB variants

8 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2228145	IL6R		0.00	0
rs4329505	IL6R	4	-0.50	1	tocilizumab
rs12083537	IL6R	3	4.50	1	tocilizumab
rs11265618	IL6R	3	2.75	1	tocilizumab
rs4845625	IL6R		0.00	0
rs4537545	IL6R		0.00	0
rs35717427	IL6R		0.00	0
rs6690230	IL6R		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: catalytic receptor — IL-6 receptor family

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
sarilumab	Binding	11.05	pKd
IL-6	Agonist	9.36	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases expression, affects expression, affects methylation	6
Acetaminophen	affects cotreatment, increases expression, decreases expression	4
bisphenol A	affects expression, decreases methylation, increases expression	3
Cisplatin	decreases expression, decreases response to substance, increases expression	3
Ethinyl Estradiol	affects expression, decreases expression, increases expression	3
Nickel	decreases expression, increases expression	3
Cyclosporine	decreases expression, increases expression	3
Aflatoxin B1	affects expression, decreases methylation, increases methylation	3
Genistein	affects cotreatment, increases expression	3
trichostatin A	affects expression, increases expression	2
arsenite	affects binding, decreases reaction, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
bisphenol S	decreases methylation	2
(+)-JQ1 compound	affects cotreatment, decreases reaction, increases expression, increases reaction	2
Arsenic	decreases expression, increases expression	2
Benzene	decreases expression, increases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases methylation, increases expression	2
Valproic Acid	increases expression	2
Zinc	increases expression, affects expression, affects cotreatment	2
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	decreases expression	1
coralyne	decreases expression	1
sotorasib	affects cotreatment, decreases expression	1
alexidine	decreases expression	1
testosterone enanthate	affects expression	1
daidzein	affects cotreatment, increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5463948	Binding	Activity against IL-6/H in the Eurofins Panlabs screen (BI) by SPA - blue shifted	Data for DCP probe BIBO3304

Cellosaurus cell lines

12 cell lines: 9 cancer cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8IH	Abcam HCT 116 IL6R KO	Cancer cell line	Male
CVCL_B8XF	Abcam MCF-7 IL6R KO	Cancer cell line	Female
CVCL_B9KR	Abcam A-549 IL6R KO	Cancer cell line	Male
CVCL_D7S8	Ubigene A-549 IL6R KO	Cancer cell line	Male
CVCL_D8N8	Ubigene HCT 116 IL6R KO	Cancer cell line	Male
CVCL_D9H5	Ubigene HEK293 IL6R KO	Transformed cell line	Female
CVCL_E0F5	Ubigene HeLa IL6R KO	Cancer cell line	Female
CVCL_E4IB	CHO-DXB11 5E27	Transformed cell line	Female
CVCL_F1U4	HyCyte THP-1 KO-hIL6R	Cancer cell line	Male
CVCL_SS46	HAP1 IL6R (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

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