IL6

Summary

IL6 (interleukin 6, HGNC:6018) is a protein-coding gene on chromosome 7p15.3, encoding Interleukin-6 (P05231). Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism. In precision oncology, IL6 Overexpression is associated with resistance to Cisplatin in Esophageal Carcinoma (CIViC Level D); 1 further curated variant–drug associations are listed below.

This gene encodes a cytokine that functions in inflammation and the maturation of B cells. In addition, the encoded protein has been shown to be an endogenous pyrogen capable of inducing fever in people with autoimmune diseases or infections. The protein is primarily produced at sites of acute and chronic inflammation, where it is secreted into the serum and induces a transcriptional inflammatory response through interleukin 6 receptor, alpha. The functioning of this gene is implicated in a wide variety of inflammation-associated disease states, including suspectibility to diabetes mellitus and systemic juvenile rheumatoid arthritis. Elevated levels of the encoded protein have been found in virus infections, including COVID-19 (disease caused by SARS-CoV-2).

Source: NCBI Gene 3569 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Kaposi sarcoma, susceptibility to (Definitive, GenCC) — +4 more curated relationships
• GWAS associations: 41
• Clinical variants (ClinVar): 355 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 52
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 2 curated variant–drug associations
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000600

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6018
Approved symbol	IL6
Name	interleukin 6
Location	7p15.3
Locus type	gene with protein product
Status	Approved
Aliases	IL-6, BSF2, HGF, HSF
Ensembl gene	ENSG00000136244
Ensembl biotype	protein_coding
OMIM	147620
Entrez	3569

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 retained_intron

ENST00000258743, ENST00000401630, ENST00000401651, ENST00000404625, ENST00000406575, ENST00000407492, ENST00000426291, ENST00000464710, ENST00000485300, ENST00000964192

RefSeq mRNA: 3 — MANE Select: NM_000600 NM_000600, NM_001318095, NM_001371096

CCDS: CCDS5375, CCDS83166, CCDS94066

Canonical transcript exons

ENST00000258743 — 5 exons

Exon	Start	End
ENSE00001128385	22731406	22731998
ENSE00003614837	22729514	22729660
ENSE00003681793	22728693	22728806
ENSE00003846286	22727200	22727281
ENSE00003892968	22727444	22727634

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 97.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 86.0043 / max 8861.8142, expressed in 1153 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77592	80.4070	1028
77594	3.9224	838
77595	0.6025	203
77593	0.4505	272
77601	0.3042	122
77600	0.1060	38
77597	0.0878	32
77598	0.0513	20
77596	0.0484	16
77599	0.0241	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	97.93	gold quality
vena cava	UBERON:0004087	97.56	gold quality
gall bladder	UBERON:0002110	95.33	gold quality
left uterine tube	UBERON:0001303	90.82	gold quality
omental fat pad	UBERON:0010414	90.73	gold quality
peritoneum	UBERON:0002358	90.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.10	gold quality
smooth muscle tissue	UBERON:0001135	88.29	gold quality
mucosa of urinary bladder	UBERON:0001259	88.17	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.10	gold quality
upper lobe of left lung	UBERON:0008952	87.97	gold quality
upper lobe of lung	UBERON:0008948	86.39	gold quality
islet of Langerhans	UBERON:0000006	85.77	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.43	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.18	gold quality
vermiform appendix	UBERON:0001154	84.69	gold quality
lung	UBERON:0002048	82.98	gold quality
trachea	UBERON:0003126	81.48	gold quality
ascending aorta	UBERON:0001496	81.29	gold quality
thoracic aorta	UBERON:0001515	80.79	gold quality
right atrium auricular region	UBERON:0006631	80.78	gold quality
pericardium	UBERON:0002407	80.09	gold quality
cardiac atrium	UBERON:0002081	79.75	gold quality
lower lobe of lung	UBERON:0008949	78.93	gold quality
muscle layer of sigmoid colon	UBERON:0035805	78.51	gold quality
lymph node	UBERON:0000029	78.34	gold quality
caecum	UBERON:0001153	78.25	gold quality
seminal vesicle	UBERON:0000998	78.19	gold quality
mucosa of stomach	UBERON:0001199	77.88	gold quality
rectum	UBERON:0001052	76.94	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	106.68
E-GEOD-130148	yes	5.02
E-MTAB-6379	no	2.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
CXCL8	Activation
GCH1	Repression
HAMP	Activation
IL10	Activation
IL1B	Activation
NOS2	Activation
TNF	Activation
VTCN1	Activation

Upstream regulators (CollecTRI, top): AHR, ANXA1, AP1, APEX1, AR, ARNT, ATF1, ATF2, ATF3, ATF4, ATF6, BACH1, BCL3, BCL6, CEBPA, CEBPB, CEBPD, CEBPG, CREB1, CTNNB1, CUX1, DDIT3, E2F3, EGR1, EGR2, EHF, EIF2AK3, ENO1, EP300, ESR1, EZH2, FLI1, FOS, FOSL1, FOSL2, FOXA1, FOXA2, FOXC1, FOXM1, FOXN1

miRNA regulators (miRDB)

58 targeting IL6, 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-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4517	99.76	69.19	1867

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• IL-6 stimulates proliferation of rat pituitary tumor cells in culture, inhibits secretion of prolactin and growth hormone and induces tyrosine phosphorylation of STAT3 in the cells. (PMID:11448119)
• Individuals genetically predisposed to produce high levels of IL-6 during aging are disadvantaged for longevity. (PMID:11500818)
• Data demonstrate that exercise activates transcription of the IL-6 gene in working skeletal muscle, a response that is dramatically enhanced when glycogen levels are low. (PMID:11687509)
• Interleukin-6 stimulates thyrotropin receptor expression in human orbital preadipocyte fibroblasts from patients with Graves’ ophthalmopathy (PMID:11716039)
• Interleukin (IL)-6 protein concentrations are increased approximately 18-fold in clinically localized prostate cancers when compared to normal prostate tissue. (PMID:11733366)
• Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. (PMID:11751408)
• Levels of IL-6 were significantly higher in patients with dyslipidemia as compared with the healthy controls (PMID:11758653)
• Interleukin-6, tumor necrosis factor alpha and interferon gamma serum levels in patients with anorexia nervosa. (PMID:11774563)
• Pancreatic periacinar myofibroblasts secrete a large amount of IL-6 in response to proinflammatory cytokines IL-17, IL-1 beta, and TNF-alpha. (PMID:11777983)
• detection in pericardial fluid in coronary pathologies (PMID:11781191)
• Function and molecular modeling of the interaction between human interleukin 6 and its HNK-1 oligosaccharide ligands (PMID:11788581)
• Expression of Interleukin-6 (IL-6) and IL-6 receptor mRNA in human bone samples from pre- and postmenopausal women. (PMID:11792588)
• biosynthesis induced by tnf-alpha or interleukin 1 beta in human fibroblast-like synoviocytes increases with cell passage (PMID:11794009)
• Heat shock factor 1 represses transcription of the IL-1beta gene through physical interaction with the nuclear factor of interleukin 6 (PMID:11801594)
• Il-6 and oncostatin M act synergistically to promote growth in a new human myeloma cell line. (PMID:11818668)
• Certoparin but not UFH led to a dose-dependent increase in IL-6 from non-stimulated PBMC. (PMID:11820460)
• NADH significantly stimulated the dose-dependent release of IL-6 from peripheral blood leukocytes.The biological relevance of these data is discussed in the context of the recent use of NADH for the treatment of several neurodegenerative disorders. (PMID:11847482)
• Increased plasma levels of interleukin-6 and interleukin-8 are observed in beta-thalassaemia major patients and may be relevant in the pathophysiology of beta-thalassaemia (PMID:11855786)
• In dengue shock syndrome pts, IL-6 was significantly associated with both activation markers of coagulation (F1+2; p < 0.03) and fibrinolysis (PAPc; p = 0.002). IL6 is involved in the onset and regulation of hemostasis (PMID:11858187)
• IL-6 a key cytokine in in vitro and in vivo response of Sertoli cells to external gamma irradiation (PMID:11884027)
• Cancer cachexia is mediated in part by the induction of IL-6-like cytokines from the spleen. (PMID:11884029)
• secretion induced by combined effects of protein kinase C and ERK activation with TFF-papetide and TNF-alpha (PMID:11884401)
• Shedding of the interleukin-6 (IL-6) receptor (gp80) determines the ability of IL-6 to induce gp130 phosphorylation in human osteoblasts. (PMID:11884403)
• The -597 G–>A and -174 G–>C polymorphisms in the promoter of the IL-6 gene are associated with hyperandrogenism. (PMID:11889177)
• polymorphism -174G/C does not contribute substantially to hyperlipidaemia and Type II diabetes mellitus in Japanese men (PMID:11914754)
• results suggest that IL-6 is a mediator of the effects of Crohn’s serum on in vitro mineralization and may be a contributing factor to the osteopenia associated with Crohn’s disease (PMID:11918227)
• TNF-alpha induced IL-6 gene expression in airway smooth muscle (ASM) cells via a nuclear factor (NF)-kappaB-dependent pathway (PMID:11919083)
• Fas engagement increases expression of interleukin-6 in human glioma cells. (PMID:11949822)
• process of cervical dilatation during parturition at term is associated with an increased expression of interleukin-1 beta, interleukin-6 and interleukin-8 mRNA in the lower uterine segment (PMID:11950481)
• Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells. (PMID:11959895)
• Secretion levels of sIL-2R, IL-6, IL-8, IL-10, and TNF-alpha, but not IL-4 and IL-12, are elevated in activated T-cells in large granular lymphocytic leukemia associated with autoimmune disorders. (PMID:11960393)
• the effects of high glucose in concert with AGII on IL-6 production in human mesangial cells and the modulation by blocking AGII (PMID:11961304)
• determine the cellular contents and concentrations of interleukin 6 (IL-6), interleukin 8 (IL-8) and tumour necrosis factor alpha (TNF-alpha) in fluids of patients with spermatocele or epididymal cyst (PMID:11966578)
• expressed in multiple sclerosis brain lesions (PMID:11984595)
• findings suggest that the IL-6prom G allele which may affect plasma IL-6 concentration might be a risk factor for sporadic AD in Japanese (PMID:11992567)
• high concentrations of IL-6 in the mid-secretory phase, the putative implantation window, and a further increase in the late secretory phase, the premenstrual period, support a role of IL-6 in the regulation of endometrial functions (PMID:12012622)
• IL-6 has a role in contributing directly to paclitaxel and doxorubicin resistance in U-2OS through a non-MDR-1 pathway. (PMID:12027404)
• secretion from acute myelogenous leukemia blasts was up-regulated by leptin (PMID:12031914)
• IL-6 induced activation of full-length LCAT promoter activity. A minimal IL-6 response element mapped within the distal promoter and was sufficient to mediate the IL-6 response (PMID:12032172)
• These results suggest that polymorphism of the IL-6 gene may be a useful marker for reduced bone mineral density. (PMID:12036196)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il6	ENSMUSG00000025746
rattus_norvegicus	Il6	ENSRNOG00000010278

Protein

Protein identifiers

Interleukin-6 — P05231 (reviewed: P05231)

Alternative names: B-cell stimulatory factor 2, CTL differentiation factor, Hybridoma growth factor, Interferon beta-2

All UniProt accessions (8): A0A8Q3SJL1, B4DNV3, B5MC14, B5MC21, B5MCZ3, C9J5B0, P05231, Q75MH2

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine with a wide variety of biological functions in immunity, tissue regeneration, and metabolism. Binds to IL6R, then the complex associates to the signaling subunit IL6ST/gp130 to trigger the intracellular IL6-signaling pathway. The interaction with the membrane-bound IL6R and IL6ST stimulates ‘classic signaling’, 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. IL6 is a potent inducer of the acute phase response. Rapid production of IL6 contributes to host defense during infection and tissue injury, but excessive IL6 synthesis is involved in disease pathology. In the innate immune response, is synthesized by myeloid cells, such as macrophages and dendritic cells, upon recognition of pathogens through toll-like receptors (TLRs) at the site of infection or tissue injury. In the adaptive immune response, is required for the differentiation of B cells into immunoglobulin-secreting cells. Plays a major role in the differentiation of CD4(+) T cell subsets. Essential factor for the development of T follicular helper (Tfh) cells that are required for the induction of germinal-center formation. Required to drive naive CD4(+) T cells to the Th17 lineage. Also required for proliferation of myeloma cells and the survival of plasmablast cells. Acts as an essential factor in bone homeostasis and on vessels directly or indirectly by induction of VEGF, resulting in increased angiogenesis activity and vascular permeability. Induces, through ’trans-signaling’ and synergistically with IL1B and TNF, the production of VEGF. Involved in metabolic controls, is discharged into the bloodstream after muscle contraction increasing lipolysis and improving insulin resistance. ‘Trans-signaling’ in central nervous system also regulates energy and glucose homeostasis. Mediates, through GLP-1, crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand. Also acts as a myokine. Plays a protective role during liver injury, being required for maintenance of tissue regeneration. Also has a pivotal role in iron metabolism by regulating HAMP/hepcidin expression upon inflammation or bacterial infection. Through activation of IL6ST-YAP-NOTCH pathway, induces inflammation-induced epithelial regeneration.

Subunit / interactions. Component of a hexamer of two molecules each of IL6, IL6R and IL6ST; first binds to IL6R to associate with the signaling subunit IL6ST. Interacts with IL6R (via the N-terminal ectodomain); this interaction may be affected by IL6R-binding with SORL1, hence decreasing IL6 cis signaling. Interacts with SORL1 (via the N-terminal ectodomain); this interaction leads to IL6 internalization and lysosomal degradation. May form a trimeric complex with the soluble SORL1 ectodomain and soluble IL6R receptor; this interaction might stabilize circulating IL6, hence promoting IL6 trans signaling.

Subcellular location. Secreted.

Tissue specificity. Produced by skeletal muscle.

Post-translational modifications. N- and O-glycosylated.

Disease relevance. Rheumatoid arthritis systemic juvenile (RASJ) [MIM:604302] An inflammatory articular disorder with systemic onset beginning before the age of 16. It represents a subgroup of juvenile arthritis associated with severe extraarticular features and occasionally fatal complications. During active phases of the disorder, patients display a typical daily spiking fever, an evanescent macular rash, lymphadenopathy, hepatosplenomegaly, serositis, myalgia and arthritis. Disease susceptibility is associated with variants affecting the gene represented in this entry. A IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in HIV-infected men.

Induction. Plasma levels are highly increased upon exercise, due to enhanced production by contracting skeletal muscles. Up-regulated by coagulation factor Xa (F10) in PAR-1 (F2R)-dependent manner in cardiac fibroblasts.

Polymorphism. Genetic variations in IL6 may be correlated with bone mineral density (BMD). Low BMD is a risk factor for osteoporotic fracture. Osteoporosis is characterized by reduced bone mineral density, disruption of bone microarchitecture, and the alteration of the amount and variety of non-collagenous proteins in bone. Osteoporotic bones are more at risk of fracture.

Similarity. Belongs to the IL-6 superfamily.

RefSeq proteins (3): NP_000591, NP_001305024, NP_001358025 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003574	IL-6-like	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily
IPR030473	IL6/GCSF/MGF_CS	Conserved_site
IPR030474	IL-6/GCSF/MGF	Family

Pfam: PF00489

UniProt features (26 total): helix 7, mutagenesis site 5, strand 4, sequence variant 3, disulfide bond 2, signal peptide 1, chain 1, turn 1, modified residue 1, glycosylation site 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
1ALU	X-RAY DIFFRACTION	1.9
7NXZ	X-RAY DIFFRACTION	2
4CNI	X-RAY DIFFRACTION	2.2
4J4L	X-RAY DIFFRACTION	2.3
4NI7	X-RAY DIFFRACTION	2.4
4O9H	X-RAY DIFFRACTION	2.42
8YWQ	X-RAY DIFFRACTION	2.51
4NI9	X-RAY DIFFRACTION	2.55
5FUC	X-RAY DIFFRACTION	2.7
4ZS7	X-RAY DIFFRACTION	2.93
8YWR	X-RAY DIFFRACTION	2.93
8QY5	ELECTRON MICROSCOPY	3.1
8QY6	ELECTRON MICROSCOPY	3.16
8D82	ELECTRON MICROSCOPY	3.22
1P9M	X-RAY DIFFRACTION	3.65
1IL6	SOLUTION NMR
2IL6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05231-F1	86.05	0.67

Antibody-complex structures (SAbDab): 6 — 4CNI, 4O9H, 4ZS7, 5FUC, 8YWQ, 8YWR

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 (1): 81

Disulfide bonds (2): 72–78, 101–111

Glycosylation sites (1): 73

Mutagenesis-validated functional residues (5):

Position	Phenotype
185	no loss of activity.
204	87% loss of activity.
210	loss of activity.
212	loss of activity.
173	almost no loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-1059683	Interleukin-6 signaling
R-HSA-110056	MAPK3 (ERK1) activation
R-HSA-112411	MAPK1 (ERK2) activation
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-6783783	Interleukin-10 signaling
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-8853884	Transcriptional Regulation by VENTX
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production
R-HSA-9662834	CD163 mediating an anti-inflammatory response
R-HSA-9958825	Activation of STAT3 by cadherin engagement

MSigDB gene sets: 1439 (showing top): PID_SHP2_PATHWAY, GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE45365_NK_CELL_VS_BCELL_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, REACTOME_INTERLEUKIN_6_SIGNALING, CREL_01, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, MODULE_92, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, AP1_01, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_LIPID_STORAGE

GO Biological Process (95): neutrophil apoptotic process (GO:0001781), germinal center B cell differentiation (GO:0002314), hepatic immune response (GO:0002384), neutrophil mediated immunity (GO:0002446), monocyte chemotaxis (GO:0002548), positive regulation of immunoglobulin production (GO:0002639), positive regulation of acute inflammatory response (GO:0002675), positive regulation of leukocyte chemotaxis (GO:0002690), acute-phase response (GO:0006953), inflammatory response (GO:0006954), humoral immune response (GO:0006959), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), vascular endothelial growth factor production (GO:0010573), regulation of vascular endothelial growth factor production (GO:0010574), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of gene expression (GO:0010628), positive regulation of epithelial to mesenchymal transition (GO:0010718), negative regulation of lipid storage (GO:0010888), response to activity (GO:0014823), cytokine-mediated signaling pathway (GO:0019221), platelet activation (GO:0030168), endocrine pancreas development (GO:0031018), neuron projection development (GO:0031175), response to peptidoglycan (GO:0032494), negative regulation of chemokine production (GO:0032682), positive regulation of chemokine production (GO:0032722), positive regulation of interleukin-1 beta production (GO:0032731), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-17 production (GO:0032740), positive regulation of interleukin-21 production (GO:0032745), positive regulation of interleukin-6 production (GO:0032755), positive regulation of interleukin-8 production (GO:0032757), positive regulation of tumor necrosis factor production (GO:0032760), negative regulation of collagen biosynthetic process (GO:0032966), positive regulation of peptidyl-serine phosphorylation (GO:0033138), maintenance of blood-brain barrier (GO:0035633), positive regulation of T cell proliferation (GO:0042102), glucose homeostasis (GO:0042593)

GO Molecular Function (6): cytokine activity (GO:0005125), interleukin-6 receptor binding (GO:0005138), growth factor activity (GO:0008083), identical protein binding (GO:0042802), signaling receptor binding (GO:0005102), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), interleukin-6 receptor complex (GO:0005896)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
RAF-independent MAPK1/3 activation	2
Signaling by Interleukins	2
Anti-inflammatory response favouring Leishmania parasite infection	2
Interleukin-6 family signaling	1
Cellular Senescence	1
Metabolism of proteins	1
Generic Transcription Pathway	1
Post-translational protein modification	1
Adherens junctions interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
leukocyte chemotaxis	2
acute inflammatory response	2
cell population proliferation	2
regulation of cell population proliferation	2
negative regulation of cellular process	2
vascular endothelial growth factor production	2
receptor ligand activity	2
protein binding	2
neutrophil homeostasis	1
inflammatory cell apoptotic process	1
myeloid cell apoptotic process	1
leukocyte apoptotic process	1
mature B cell differentiation involved in immune response	1
organ or tissue specific immune response	1
myeloid leukocyte mediated immunity	1
mononuclear cell migration	1
myeloid leukocyte migration	1
immunoglobulin production	1
regulation of immunoglobulin production	1
positive regulation of production of molecular mediator of immune response	1
regulation of acute inflammatory response	1
positive regulation of inflammatory response	1
positive regulation of leukocyte migration	1
regulation of leukocyte chemotaxis	1
positive regulation of chemotaxis	1
defense response	1
immune response	1
cell surface receptor signaling pathway via STAT	1
positive regulation of cellular process	1
cytokine production	1
regulation of cytokine production	1
positive regulation of cytokine production	1
regulation of vascular endothelial growth factor production	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial to mesenchymal transition	1
regulation of epithelial to mesenchymal transition	1
positive regulation of cell differentiation	1
positive regulation of multicellular organismal process	1

Protein interactions and networks

STRING

9188 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL6	IL2	P01585	999
IL6	IL6R	P08887	999
IL6	IL3	P08700	998
IL6	TNFRSF1A	P19438	997
IL6	IL6ST	P40189	997
IL6	IL1R1	P14778	997
IL6	IL1B	P01584	990
IL6	IL9	P15248	990
IL6	TNF	P01375	989
IL6	IL10	P22301	988
IL6	IL7	P13232	984
IL6	IFNG	P01579	982
IL6	IL4	P05112	979
IL6	IL5	P05113	977
IL6	CXCL8	P10145	977

IntAct

35 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
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
IL6	IL6R	psi-mi:“MI:0407”(direct interaction)	0.600
IL6R	IL6	psi-mi:“MI:0407”(direct interaction)	0.600
IL6R	IL6	psi-mi:“MI:0914”(association)	0.600
IL6	SORL1	psi-mi:“MI:0407”(direct interaction)	0.570
SORL1	IL6	psi-mi:“MI:0403”(colocalization)	0.570
SORL1	IL6	psi-mi:“MI:0915”(physical association)	0.570
SORT1	IL6	psi-mi:“MI:0407”(direct interaction)	0.570
SORT1	IL6	psi-mi:“MI:0403”(colocalization)	0.570
SORT1	IL6	psi-mi:“MI:0915”(physical association)	0.570
IL6	IL6	psi-mi:“MI:0407”(direct interaction)	0.560
IL6	ZBTB16	psi-mi:“MI:2364”(proximity)	0.520
FAM20C	IL6	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
FCGR3B	IL6	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (16): ZBTB16 (Co-localization), HRH1 (Co-localization), IL6R (Reconstituted Complex), IL6 (Reconstituted Complex), IL6 (Synthetic Lethality), IL6 (Reconstituted Complex), IL6 (Affinity Capture-RNA), SH3GL2 (Two-hybrid), IL6 (Affinity Capture-Western), JAK1 (Positive Genetic), IL6 (Negative Genetic), IL6 (Affinity Capture-RNA), USP14 (Affinity Capture-Western), IL6 (Affinity Capture-Western), HNRNPD (Protein-RNA)

ESM2 similar proteins: A0S0B0, A3FBE9, B6CKP4, O73848, P01241, P01244, P05231, P06880, P08505, P08998, P09321, P09586, P09611, P0DML2, P0DML3, P11228, P14188, P16038, P19795, P20294, P20607, P22077, P26441, P37886, P41683, P43431, P46650, P51494, P51642, P58343, P58756, P58757, P79341, Q07370, Q0GGL7, Q14406, Q25BC2, Q28819, Q2XNF5, Q5I6E3

Diamond homologs: A3FBE9, O35736, P05231, P08505, P20607, P26892, P26893, P29455, P41323, P41683, P41693, P46650, P51494, P79341, Q25BC2, Q28319, Q28747, Q28819, Q2MH06, Q5I6E3, Q6V919, Q865W7, Q865X6, Q8MKH0, Q90YI0, Q95181, Q9MZR1, Q9XT80

SIGNOR signaling

37 interactions.

A	Effect	B	Mechanism
IL6	up-regulates	IL6R	binding
NFATC1	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
NFATC2	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
NFATC3	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
IL6	“down-regulates quantity by repression”	GCH1	“transcriptional regulation”
“A9/b1 integrin”	“up-regulates quantity by expression”	IL6
NfKb-p65/p50	up-regulates	IL6	“transcriptional regulation”
ATF2	up-regulates	IL6	“transcriptional regulation”
AP1	up-regulates	IL6	“transcriptional regulation”
IL6	“up-regulates activity”	IL6R	binding
Degranulation	“up-regulates quantity”	IL6
NfKb-p65/p50	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
SRF	up-regulates	IL6
TP53	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
TLR5	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
IL6	up-regulates	Inflammation
S	“up-regulates quantity”	IL6
chloroquine	“down-regulates quantity”	IL6
IL1B	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
TNF	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
RELA	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
“Activated PSC”	up-regulates	IL6
IFNG	“up-regulates activity”	IL6	“transcriptional regulation”
IL6	“up-regulates activity”	IL6ST	binding
IRF3	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
PPP3CA	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
PPP3CB	“up-regulates quantity by expression”	IL6	“transcriptional regulation”
PPP3CC	“up-regulates quantity by expression”	IL6	“transcriptional regulation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	156
Likely benign	118
Benign	38

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
14949	NM_000601.6(HGF):c.495G>A (p.Ser165=)	Pathogenic
14951	NM_000601.6(HGF):c.482+1991_482+2000del	Pathogenic
2044269	NM_000601.6(HGF):c.1953_1954insGAATGAGT (p.Leu652delinsGluTer)	Pathogenic
2821398	NM_000601.6(HGF):c.1048C>T (p.Arg350Ter)	Pathogenic
4691870	NM_000601.6(HGF):c.1091G>A (p.Trp364Ter)	Pathogenic
4728122	NM_000601.6(HGF):c.6G>A (p.Trp2Ter)	Pathogenic
2507239	NM_000601.6(HGF):c.84T>G (p.Tyr28Ter)	Likely pathogenic
4773543	NM_000601.6(HGF):c.1616+1G>A	Likely pathogenic

SpliceAI

526 predictions. Top by Δscore:

Variant	Effect	Δscore
7:22727632:G:GT	donor_gain	1.0000
7:22728688:CCCA:C	acceptor_loss	1.0000
7:22728689:CCAG:C	acceptor_loss	1.0000
7:22728690:CAG:C	acceptor_loss	1.0000
7:22728691:A:AG	acceptor_gain	1.0000
7:22728692:G:GT	acceptor_gain	1.0000
7:22728692:GA:G	acceptor_gain	1.0000
7:22728692:GAC:G	acceptor_gain	1.0000
7:22728692:GACA:G	acceptor_gain	1.0000
7:22728692:GACAT:G	acceptor_gain	1.0000
7:22728802:ATGAG:A	donor_loss	1.0000
7:22728803:TGAGG:T	donor_loss	1.0000
7:22728804:G:GT	donor_gain	1.0000
7:22728804:GAGGT:G	donor_loss	1.0000
7:22728805:AGGTA:A	donor_loss	1.0000
7:22728807:G:GC	donor_loss	1.0000
7:22728808:T:G	donor_loss	1.0000
7:22729509:CTTA:C	acceptor_loss	1.0000
7:22729510:TTA:T	acceptor_loss	1.0000
7:22729511:TA:T	acceptor_loss	1.0000
7:22729512:A:AG	acceptor_gain	1.0000
7:22729512:A:C	acceptor_loss	1.0000
7:22729512:AG:A	acceptor_gain	1.0000
7:22729513:G:GG	acceptor_gain	1.0000
7:22729513:GG:G	acceptor_gain	1.0000
7:22729513:GGA:G	acceptor_gain	1.0000
7:22729513:GGAGA:G	acceptor_gain	1.0000
7:22729622:A:G	donor_gain	1.0000
7:22729661:G:A	donor_loss	1.0000
7:22727282:G:GG	donor_gain	0.9900

AlphaMissense

1395 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:22731535:T:C	F201L	0.993
7:22731537:C:A	F201L	0.993
7:22731537:C:G	F201L	0.993
7:22731547:A:C	S205R	0.990
7:22731549:C:A	S205R	0.990
7:22731549:C:G	S205R	0.990
7:22729553:T:C	F122L	0.989
7:22729555:T:A	F122L	0.989
7:22729555:T:G	F122L	0.989
7:22728783:T:A	C101S	0.987
7:22728784:G:C	C101S	0.987
7:22728783:T:C	C101R	0.982
7:22729522:C:G	C111W	0.981
7:22729545:T:C	L119P	0.980
7:22729520:T:C	C111R	0.977
7:22728798:T:C	F106L	0.976
7:22728800:C:A	F106L	0.976
7:22728800:C:G	F106L	0.976
7:22729521:G:A	C111Y	0.975
7:22731539:T:C	L202P	0.975
7:22729520:T:A	C111S	0.974
7:22729521:G:C	C111S	0.974
7:22728785:C:G	C101W	0.968
7:22731512:T:C	L193P	0.967
7:22731536:T:G	F201C	0.967
7:22728760:C:A	P93Q	0.966
7:22731489:G:C	W185C	0.966
7:22731489:G:T	W185C	0.966
7:22728784:G:A	C101Y	0.965
7:22729554:T:G	F122C	0.965

dbSNP variants (sampled 300 via entrez): RS1000829843 (7:22730527 A>G), RS1000900537 (7:22730773 A>G), RS1001486170 (7:22732209 T>A,C,G), RS1002148681 (7:22727152 T>C), RS1002525182 (7:22731642 A>C), RS1002577527 (7:22731988 T>A,C), RS1002676051 (7:22727603 T>C), RS1002746567 (7:22725521 C>G,T), RS1003092646 (7:22725239 A>G), RS1003532198 (7:22730128 A>T), RS1003584519 (7:22730327 A>T), RS1004035389 (7:22727862 C>A,T), RS1004089176 (7:22728190 G>A), RS1004777340 (7:22729844 C>G), RS1005093256 (7:22726680 T>C)

Disease associations

OMIM: gene MIM:147620 | disease phenotypes: MIM:608265, MIM:244400

GenCC curated gene-disease

Disease	Classification	Inheritance
Kaposi sarcoma, susceptibility to	Definitive	Autosomal dominant
autosomal recessive nonsyndromic hearing loss 39	Strong	Autosomal recessive
lymphedema	Strong	Autosomal dominant
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Moderate	AR

Mondo (9): hearing loss disorder (MONDO:0005365), autosomal recessive nonsyndromic hearing loss 39 (MONDO:0012003), primary ciliary dyskinesia (MONDO:0016575), Kaposi’s sarcoma (MONDO:0005055), cholangiocarcinoma (MONDO:0019087), sensorineural hearing loss disorder (MONDO:0020678), hearing loss, autosomal recessive (MONDO:0019588), lymphedema (MONDO:0019297), Kaposi sarcoma, susceptibility to (MONDO:0007845)

Orphanet (4): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Primary ciliary dyskinesia (Orphanet:244), Kaposi sarcoma (Orphanet:33276), Cholangiocarcinoma (Orphanet:70567)

HPO phenotypes

52 total (30 of 52 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000099	Glomerulonephritis
HP:0000103	Polyuria
HP:0000399	Prelingual sensorineural hearing impairment
HP:0000819	Diabetes mellitus
HP:0000855	Insulin resistance
HP:0000938	Osteopenia
HP:0000969	Edema
HP:0000988	Skin rash
HP:0001034	Hypermelanotic macule
HP:0001369	Arthritis
HP:0001386	Joint swelling
HP:0001442	Typified by somatic mosaicism
HP:0001510	Growth delay
HP:0001701	Pericarditis
HP:0001744	Splenomegaly
HP:0001824	Weight loss
HP:0001945	Fever
HP:0001959	Polydipsia
HP:0001993	Ketoacidosis
HP:0002014	Diarrhea
HP:0002027	Abdominal pain
HP:0002037	Inflammation of the large intestine
HP:0002202	Pleural effusion
HP:0002240	Hepatomegaly
HP:0002408	Cerebral arteriovenous malformation
HP:0002591	Polyphagia
HP:0002664	Neoplasm
HP:0002716	Lymphadenopathy

GWAS associations

41 associations (top):

Study	Trait	p-value
GCST000933_2	C-reactive protein	4.000000e-11
GCST001066_8	Dialysis-related mortality	4.000000e-06
GCST001356_29	Gout	1.000000e-07
GCST002147_24	Fibrinogen	7.000000e-09
GCST002731_1	Endothelial growth factor levels	4.000000e-19
GCST003137_1	Cerebrospinal fluid clusterin levels in APOEe4- carriers	7.000000e-08
GCST003425_1	Longevity	2.000000e-09
GCST004449_15	Hepatocyte growth factor levels	3.000000e-14
GCST004844_1	Gestational age at birth (maternal effect)	1.000000e-07
GCST004845_1	Spontaneous preterm birth (maternal effect)	3.000000e-08
GCST004923_3	Tuberculosis	3.000000e-08
GCST005170_30	Intraocular pressure	6.000000e-12
GCST005528_25	Juvenile idiopathic arthritis (oligoarticular or rheumatoid factor-negative polyarticular)	3.000000e-08
GCST005790_6	Rosacea symptom severity	1.000000e-07
GCST006412_66	Intraocular pressure	6.000000e-13
GCST006575_15	Takayasu arteritis	2.000000e-07
GCST006575_25	Takayasu arteritis	7.000000e-09
GCST006585_2668	Blood protein levels	1.000000e-07
GCST006629_59	Pulse pressure	2.000000e-25
GCST006988_157	Blond vs. brown/black hair color	7.000000e-50
GCST007269_269	Pulse pressure	2.000000e-19
GCST007614_15	C-reactive protein levels	8.000000e-14
GCST007798_82	Asthma	3.000000e-06
GCST007800_90	Asthma (childhood onset)	3.000000e-08
GCST007994_18	Asthma (age of onset)	8.000000e-06
GCST007995_51	Asthma (childhood onset)	5.000000e-10
GCST008362_166	Birth weight	2.000000e-09
GCST008363_55	Offspring birth weight	6.000000e-07
GCST008363_56	Offspring birth weight	2.000000e-09
GCST008474_7	Peripheral artery disease	4.000000e-11

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004458	C-reactive protein measurement
EFO:0005112	gestational age
EFO:0005939	parental genotype effect measurement
EFO:0006917	spontaneous preterm birth
EFO:0004695	intraocular pressure measurement
EFO:0009180	rosacea severity measurement
EFO:0005763	pulse pressure measurement
EFO:0003924	hair color
EFO:0004344	birth weight
EFO:0000266	aortic stenosis

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D018281	Cholangiocarcinoma	C04.557.470.200.025.450
D002925	Ciliary Motility Disorders	C08.200; C09.150; C16.131.077.245.500; C16.320.184.500
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D007619	Kartagener Syndrome	C08.127.384.500; C08.200.531; C08.695.501; C09.150.531; C14.240.400.280.500; C14.280.400.280.500; C16.131.077.245.500.531; C16.131.240.400.280.500; C16.131.740.501; C16.131.810.250.500; C16.320.184.500.531; C16.320.480
D008209	Lymphedema	C15.604.496
D012514	Sarcoma, Kaposi	C01.925.256.466.860; C04.557.450.795.850; C04.557.645.750
C564609	Deafness, Autosomal Recessive (supp.)
C564265	Deafness, Autosomal Recessive 39 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1795129 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 140,841 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL131	PREDNISOLONE	4	140,604
CHEMBL3137316	FOSDAGROCORAT	2	209
CHEMBL3358954	BI 653048	1	28

Clinical evidence (CIViC)

Drug × variant × indication: 2 predictive associations from 2 curated evidence items.

Variant	Therapy	Indication	Effect	Level	CIViC
IL6 Overexpression	Cisplatin	Esophageal Carcinoma	Resistance	CIViC D	EID7851
IL6 Overexpression	Bazedoxifene	Rhabdomyosarcoma	Resistance	CIViC D	EID7956

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

PharmGKB clinical annotations

5 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs10499563	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Inflammatory Bowel Diseases;Ulcerative Colitis
rs1800795	Efficacy	3	fenofibrate	Cardiovascular Disease
rs1800795	Efficacy	3	adalimumab;etanercept;infliximab	Rheumatoid arthritis
rs1800795	Toxicity	3	peginterferon alfa-2b;ribavirin	Chronic hepatitis C virus infection
rs1800795	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Psoriasis

PharmGKB variants

10 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1524107	IL6		0.00	0
rs1800795	IL6	3	2.25	4	fenofibrate;Tumor necrosis factor alpha (TNF-alpha) inhibitors;adalimumab;etanercept;infliximab;peginterferon alfa-2b;ribavirin
rs1800796	IL6		0.00	0
rs1800797	IL6		0.00	0
rs2066992	IL6		0.00	0
rs2069837	IL6		0.00	0
rs10242595	IL6		0.00	0
rs10499563	IL6	3	3.50	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs2069840	IL6		0.00	0
rs2069835	IL6		0.00	0

Binding affinities (BindingDB)

24 measured of 29 human assays (29 total across all organisms); most potent 24 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(4bS,7R,8aR)-4b-benzyl-N-(3,5-dimethylpyrazin-2-yl)-7-hydroxy-7-(trifluoromethyl)-5,6,8,8a,9,10-hexahydrophenanthrene-2-carboxamide	IC50	0.35 nM	US-8901310: Tricyclic compounds, compositions, and methods
(4bS,7R,8aS)-4b-benzyl-7-hydroxy-N-(2-methyl-3-pyridinyl)-10-oxo-7-(trifluoromethyl)-6,8,8a,9-tetrahydro-5H-phenanthrene-2-carboxamide	IC50	1.18 nM	US-8901310: Tricyclic compounds, compositions, and methods
(4bS,7S,8aR)-4b-benzyl-7-hydroxy-N-(2-methyl-3-pyridinyl)-7-(3,3,3-trifluoropropyl)-5,6,8,8a,9,10-hexahydrophenanthrene-2-carboxamide	IC50	1.22 nM	US-8901310: Tricyclic compounds, compositions, and methods
(4bS,7R,8aR,10R)-4b-benzyl-7,10-dihydroxy-N-(2-methyl-3-pyridinyl)-7-(trifluoromethyl)-5,6,8,8a,9,10-hexahydrophenanthrene-2-carboxamide	IC50	1.9 nM	US-8901310: Tricyclic compounds, compositions, and methods
(4bS,7R,8aR)-4b-benzyl-7-hydroxy-N-(4-methyl-3-pyridinyl)-7-(trifluoromethyl)-5,6,8,8a,9,10-hexahydrophenanthrene-2-carboxamide	IC50	2.06 nM	US-8901310: Tricyclic compounds, compositions, and methods
(4bS,7R,8aR)-4b-benzyl-7-hydroxy-N-(2-methyl-1-oxidopyridin-1-ium-3-yl)-7-(trifluoromethyl)-5,6,8,8a,9,10-hexahydrophenanthrene-2-carboxamide	IC50	2.13 nM	US-8901310: Tricyclic compounds, compositions, and methods
(4bS,7S,8aR)-4b-benzyl-N-(2,4-dimethylpyrimidin-5-yl)-7-hydroxy-7-(3,3,3-trifluoropropyl)-5,6,8,8a,9,10-hexahydrophenanthrene-2-carboxamide	IC50	4.58 nM	US-8901310: Tricyclic compounds, compositions, and methods
(4bS,7R,8aR)-4b-benzyl-7-(difluoromethyl)-7-hydroxy-N-(2-methyl-3-pyridinyl)-5,6,8,8a,9,10-hexahydrophenanthrene-2-carboxamide	IC50	8.03 nM	US-8901310: Tricyclic compounds, compositions, and methods
(4bS,7R,8aS)-4b-benzyl-7-hydroxy-N-(2-methyl-3-pyridinyl)-7-(trifluoromethyl)-5,6,8,8a-tetrahydrophenanthrene-2-carboxamide	IC50	9.12 nM	US-8901310: Tricyclic compounds, compositions, and methods
(S)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one	IC50	13 nM	US-10435379: [4-(1,3,3-trimethyl-2-OXO-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or salt thereof
(R)-7-[4-(3-cyano-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one	IC50	14 nM	US-10435379: [4-(1,3,3-trimethyl-2-OXO-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or salt thereof
(S)-7-[4-(2,4-dihydroxybutyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methyl-phenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one	IC50	15 nM	US-10435379: [4-(1,3,3-trimethyl-2-OXO-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or salt thereof
CC-220 (Compound 6)	IC50	28 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
(S)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxypropyl)oxy-2-methoxy-phenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one	IC50	33 nM	US-10435379: [4-(1,3,3-trimethyl-2-OXO-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or salt thereof
(R)-8-(5-fluoro-2-methylphenoxymethyl)-7-[4-(2-hydroxybutyl)oxy-2-methoxyphenyl]-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one	IC50	34 nM	US-10435379: [4-(1,3,3-trimethyl-2-OXO-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or salt thereof
[(2R,4aS,10aR)-4a-benzyl-7-[(2-methyl-3-pyridinyl)carbamoyl]-2-(trifluoromethyl)-1,3,4,9,10,10a-hexahydrophenanthren-2-yl] dihydrogen phosphate	IC50	42 nM	US-8901310: Tricyclic compounds, compositions, and methods
7-[4-(3-t-butoxycarbonyl-2-hydroxypropyl)oxy-2-methoxyphenyl]-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one	IC50	83 nM	US-10435379: [4-(1,3,3-trimethyl-2-OXO-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or salt thereof
8-(5-fluoro-2-methylphenoxymethyl)-7-(5-hydroxy-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one	IC50	93 nM	US-10435379: [4-(1,3,3-trimethyl-2-OXO-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or salt thereof
8-(5-fluoro-2-methylphenoxymethyl)-7-(5-hydroxymethyl-2-methoxyphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one	IC50	123 nM	US-10435379: [4-(1,3,3-trimethyl-2-OXO-3,4-dihydro-1H-quinoxalin-7-yl)phenoxy]ethyloxy compound or salt thereof
3-(4-((4-(morpholinomethyl)benzyl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione	IC50	190 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
19171-19-8	IC50	230 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
(1S,2R,10S,11S,14R,15S,17S)-14,17-dihydroxy-14-(2-hydroxyacetyl)-2,15-dimethyltetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadeca-3,6-dien-5-one	IC50	251 nM	US-10196374: 1-alkyl-6-oxo-1,6-dihydropyridin-3-yl compounds and use as SGRM modulators
3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione	IC50	300 nM	US-9694015: Methods for the treatment of locally advanced breast cancer
(R)-3-(4-((4-(morpholinomethyl)benzyl)-oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione	IC50	450 nM	US-9694015: Methods for the treatment of locally advanced breast cancer

ChEMBL bioactivities

142 potent at pChembl≥5 of 145 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.96	IC50	1.1	nM	CHEMBL3647441
8.96	IC50	1.1	nM	CHEMBL3647443
8.89	IC50	1.3	nM	CHEMBL3647442
8.68	IC50	2.1	nM	CHEMBL3647445
8.60	EC50	2.5	nM	CHEMBL5967615
8.55	IC50	2.8	nM	CHEMBL3647447
8.42	EC50	3.77	nM	CHEMBL5993886
8.42	EC50	3.8	nM	CHEMBL5757665
8.40	IC50	4	nM	CHEMBL3647440
8.38	IC50	4.2	nM	PREDNISOLONE
8.37	IC50	4.3	nM	CHEMBL3647446
8.31	EC50	4.9	nM	CHEMBL5787912
8.29	EC50	5.11	nM	CHEMBL5977638
8.24	EC50	5.81	nM	CHEMBL5790478
8.23	EC50	5.91	nM	CHEMBL5992328
8.18	EC50	6.62	nM	CHEMBL6041191
8.16	EC50	6.9	nM	CHEMBL5907906
8.15	IC50	7	nM	CHEMBL3647444
8.12	EC50	7.55	nM	CHEMBL5746816
8.12	EC50	7.5	nM	CHEMBL5948820
8.12	EC50	7.6	nM	CHEMBL5778223
8.11	EC50	7.8	nM	CHEMBL5950488
8.09	EC50	8.14	nM	CHEMBL5865451
8.02	EC50	9.57	nM	CHEMBL5863568
8.00	EC50	10.1	nM	CHEMBL5757312
7.98	EC50	10.4	nM	CHEMBL6057462
7.97	EC50	10.7	nM	CHEMBL5935960
7.96	EC50	11	nM	CHEMBL6025451
7.92	EC50	12	nM	CHEMBL5801959
7.90	EC50	12.6	nM	CHEMBL5787912
7.89	IC50	13	nM	CHEMBL5854612
7.89	EC50	13	nM	CHEMBL6040007
7.89	EC50	13	nM	CHEMBL5878671
7.85	IC50	14	nM	CHEMBL6062967
7.85	EC50	14	nM	CHEMBL5769037
7.85	EC50	14	nM	CHEMBL5972079
7.85	EC50	14	nM	CHEMBL5766714
7.84	EC50	14.4	nM	CHEMBL5753489
7.84	EC50	14.3	nM	CHEMBL5926850
7.84	EC50	14.4	nM	CHEMBL5856275
7.82	IC50	15	nM	CHEMBL5842809
7.82	EC50	15	nM	CHEMBL5753489
7.82	EC50	15	nM	CHEMBL5849962
7.79	EC50	16.1	nM	CHEMBL5947975
7.77	EC50	17	nM	CHEMBL5845465
7.76	EC50	17.3	nM	CHEMBL5949769
7.75	EC50	17.6	nM	CHEMBL5936570
7.72	EC50	18.9	nM	CHEMBL5943152
7.72	EC50	19	nM	CHEMBL5985963
7.72	EC50	19	nM	CHEMBL5745822

PubChem BioAssay actives

8 with measured affinity, of 29 total; 8 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,4S,4aR,10bS)-3,4,8,10-tetrahydroxy-2-(hydroxymethyl)-9-methoxy-3,4,4a,10b-tetrahydro-2H-pyrano[3,2-c]isochromen-6-one	1464042: Inhibition of IL6 (unknown origin)	ic50	0.2080	uM
ethyl (2Z)-7-methyl-2-[(4-morpholin-4-ylphenyl)methylidene]-3-oxo-5-thiophen-2-yl-8,8a-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate	1928289: Inhibition of IL-6 (unknown origin) by ELISA assay	ic50	0.5600	uM
ethyl (2Z)-7-methyl-2-[(4-morpholin-4-ylphenyl)methylidene]-3-oxo-5-(4-prop-2-enoxyphenyl)-8,8a-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate	1928289: Inhibition of IL-6 (unknown origin) by ELISA assay	ic50	0.6000	uM
ethyl (2Z)-7-methyl-2-[(4-morpholin-4-ylphenyl)methylidene]-3-oxo-5-phenyl-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate	1928289: Inhibition of IL-6 (unknown origin) by ELISA assay	ic50	0.8600	uM
(2E,5E)-2-[[4-[3-(dimethylamino)propoxy]phenyl]methylidene]-5-[[2-(trifluoromethyl)phenyl]methylidene]cyclopentan-1-one	1928289: Inhibition of IL-6 (unknown origin) by ELISA assay	ic50	1.2800	uM
18-benzyl-4,12,12-trimethyl-6-oxa-18-azapentacyclo[13.2.1.03,7.08,17.011,16]octadeca-1(17),3(7),4,8,10,15-hexaene-2,14-dione	1928289: Inhibition of IL-6 (unknown origin) by ELISA assay	ic50	1.6300	uM
(2E,5E)-2-[(4-hydroxy-3-methoxyphenyl)methylidene]-5-[[2-(trifluoromethyl)phenyl]methylidene]cyclopentan-1-one	1928289: Inhibition of IL-6 (unknown origin) by ELISA assay	ic50	1.9990	uM
N-[2-(4-ethylanilino)-1,3-benzoxazol-5-yl]benzamide	1452825: Inhibition of IL-6 signaling pathway in human HepG2 cells transfected with p-STAT3-Luc assessed as reduction in IL-6 induced STAT3 phosphorylation preincubated for 1 hr followed by IL-6 induction measured after 10 mins by immunoblot analysis	ic50	5.8000	uM

CTD chemical–gene interactions

1136 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects response to substance, affects secretion, decreases expression, increases secretion, affects expression (+8 more)	186
Particulate Matter	increases expression, decreases reaction, affects secretion, affects reaction, affects expression (+7 more)	100
Resveratrol	decreases secretion, affects cotreatment, increases expression, increases secretion, affects expression (+8 more)	42
Air Pollutants	affects secretion, affects cotreatment, decreases reaction, increases reaction, affects reaction (+5 more)	37
Vehicle Emissions	affects response to substance, decreases secretion, decreases reaction, increases abundance, affects reaction (+7 more)	37
SB 203580	affects cotreatment, decreases secretion, decreases response to substance, increases expression, increases reaction (+5 more)	32
Tetradecanoylphorbol Acetate	decreases reaction, increases expression, affects reaction, increases secretion, increases reaction (+2 more)	31
Dexamethasone	decreases reaction, decreases response to substance, increases secretion, increases expression, decreases secretion (+6 more)	29
Acetylcysteine	decreases expression, affects cotreatment, decreases reaction, increases expression, increases reaction (+3 more)	26
bisphenol A	decreases expression, decreases reaction, increases expression, increases reaction, affects cotreatment (+5 more)	24
sodium arsenite	increases activity, decreases reaction, increases secretion, affects reaction, increases abundance (+4 more)	21
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases response to substance, decreases reaction, increases expression, increases secretion, increases abundance (+2 more)	21
Quercetin	increases expression, decreases expression, decreases reaction, increases secretion, affects binding (+4 more)	21
lipopolysaccharide, Escherichia coli O111 B4	affects cotreatment, decreases activity, decreases reaction, increases expression, increases response to substance (+4 more)	20
Tobacco Smoke Pollution	decreases reaction, increases secretion, increases reaction, decreases expression, increases phosphorylation (+5 more)	20
Cadmium Chloride	decreases reaction, increases abundance, increases secretion, affects expression, decreases expression (+3 more)	19
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases expression, increases secretion, affects cotreatment, decreases activity, decreases response to substance (+1 more)	18
Hydrogen Peroxide	decreases reaction, increases expression, increases reaction, affects binding, affects cotreatment (+4 more)	18
Mustard Gas	affects reaction, affects expression, increases reaction, increases secretion, decreases reaction (+1 more)	18
Glucose	increases secretion, affects cotreatment, increases reaction, affects expression, affects reaction (+2 more)	17
Ozone	affects cotreatment, increases expression, decreases reaction, increases abundance, increases reaction (+2 more)	17
Calcimycin	affects cotreatment, decreases reaction, increases expression, increases reaction, increases secretion	15
Cadmium	decreases reaction, increases expression, affects expression, increases reaction, increases secretion (+3 more)	15
Curcumin	increases expression, increases secretion, increases abundance, affects cotreatment, decreases expression (+2 more)	15
Silicon Dioxide	decreases reaction, increases secretion, increases expression, increases reaction, affects reaction	15
pyrazolanthrone	decreases reaction, increases expression, increases secretion, affects cotreatment, increases reaction	14
Estradiol	affects expression, decreases reaction, increases secretion, affects reaction, decreases secretion (+7 more)	14
1-Methyl-4-phenylpyridinium	increases reaction, decreases reaction, increases expression, increases secretion, affects reaction (+1 more)	14
nickel sulfate	increases secretion, affects reaction, increases expression, affects cotreatment, decreases reaction	12
lipopolysaccharide, E coli O55-B5	decreases reaction, increases expression, increases secretion, increases reaction, affects binding (+1 more)	12

ChEMBL screening assays

16 unique, capped per target: 16 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1809407	Binding	Inhibition of IL-6 at 4 uM	Discovery of N-(1-ethylpropyl)-[3-methoxy-5-(2-methoxy-4-trifluoromethoxyphenyl)-6-methyl-pyrazin-2-yl]amine 59 (NGD 98-2): an orally active corticotropin releasing factor-1 (CRF-1) receptor antagonist. — J Med Chem

Cellosaurus cell lines

7 cell lines: 5 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A1SE	S6B45	Cancer cell line	Female
CVCL_B1FZ	Abcam A-549 IL6 KO	Cancer cell line	Male
CVCL_D7S7	Ubigene A-549 IL6 KO	Cancer cell line	Male
CVCL_E0F4	Ubigene HeLa IL6 KO	Cancer cell line	Female
CVCL_E6UB	Genomeditech HEK-293 H_IL6 Reporter	Transformed cell line	Female
CVCL_LF76	N263	Transformed cell line	Male
CVCL_Y023	ABC-1#IL-6	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00852930	PHASE4	COMPLETED	Low Level Laser Treatment and Breast Cancer Related Lymphedema
NCT01068431	PHASE4	COMPLETED	Short Term Effectiveness Study of Juxta-Fit Versus Trico Bandages in the Treatment of Leg Lymphedema
NCT02257970	PHASE4	COMPLETED	Lymphedema Study for Arm or Leg Lymphedema
NCT02375945	PHASE4	COMPLETED	Comparison Between a Non-elastic Falcro Device and Current Method After Total Knee Arthroplasty
NCT03584633	PHASE4	COMPLETED	Effect of Exercise on Indocyanine Green (ICG) Lymphography Imaging
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT00028951	PHASE3	COMPLETED	Fibrin Sealant in Decreasing Lymphedema Following Surgery to Remove Lymph Nodes in Patients With Cancer of the Vulva
NCT00201890	PHASE3	COMPLETED	Trial of Decongestive Lymphatic Therapy for Lymphedema in Women With Breast Cancer DELTA STUDY
NCT00577317	PHASE3	TERMINATED	Flexitouch® Home Maintenance Therapy or Standard Home Maintenance Therapy in Treating Patients With Lower-Extremity Lymphedema Caused by Treatment for Cervical Cancer, Vulvar Cancer, or Endometrial Cancer
NCT02927496	PHASE3	COMPLETED	A 24 Month Study, to Compare the Efficacy of Doxycycline vs. Placebo for Improving Filarial Lymphedema in Mali
NCT02929121	PHASE3	COMPLETED	A 24 Month Study to Compare Efficacy of Doxycycline vs Placebo for Improving Filarial Lymphedema in India
NCT02929134	PHASE3	COMPLETED	A 24 Month Study to Compare Efficacy of Doxycycline vs Placebo for Improving Filarial Lymphedema in Sri Lanka
NCT04228991	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated LocoRegional Radiotherapy in Breast Cancer
NCT06144164	PHASE3	RECRUITING	A Study of a Comprehensive Prevention Program to Reduce Lymphedema After Axillary Lymph Node Dissection in People With Breast Cancer
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00022204	PHASE2	COMPLETED	Vitamin E and Pentoxifylline in Treating Women With Lymphedema After Radiation Therapy for Breast Cancer
NCT00058851	PHASE2	COMPLETED	Massage Therapy for Breast Cancer Treatment-Related Swelling of the Arms
NCT00064857	PHASE2	COMPLETED	Pycnogenol for the Treatment of Lymphedema of the Arm in Breast Cancer Survivors
NCT00077090	PHASE2	UNKNOWN	Hyperbaric Oxygen Therapy Compared With Standard Therapy in Treating Chronic Arm Lymphedema in Patients Who Have Undergone Radiation Therapy for Cancer
NCT00155220	PHASE2	UNKNOWN	Treatment of Lymphedema: Application of the Kinesio Taping
NCT00188604	PHASE2	COMPLETED	The Use of Selenium to Treat Secondary Lymphedema - Breast Cancer
NCT00214032	PHASE2	COMPLETED	Pycnogenol for the Treatment of Lymphedema
NCT00589121	PHASE2	COMPLETED	Image-Guided Radiation Therapy in Treating Patients With Primary Soft Tissue Sarcoma of the Shoulder, Arm, Hip, or Leg
NCT00827372	PHASE2	COMPLETED	A Study of Vascular Endothelial Growth Factor (VEGF) Inhibition in Patients With Unilateral Upper Extremity Lymphedema Following Treatment for Cancer
NCT01003951	PHASE2	COMPLETED	Acupuncture for the Treatment of Chronic Lymphedema
NCT01276054	PHASE2	TERMINATED	Sentinel and/or Axillary Lymph Node Biopsy With or Without Axillary Reverse Mapping in Reducing Incidence and Severity of Arm Lymphedema in Stage 0-2 Patients.
NCT01318785	PHASE2	UNKNOWN	Therapeutical Assessment of Compression Armsleeves for Lymphatic Indications
NCT01406769	PHASE2	COMPLETED	Bioimpedance Spectroscopy in Detecting Lower-Extremity Lymphedema in Patients With Stage I, Stage II, Stage III, or Stage IV Vulvar Cancer Undergoing Surgery and Lymphadenectomy
NCT02700529	PHASE2	COMPLETED	Ubenimex in Adult Patients With Lymphedema of The Lower Limb (ULTRA)
NCT02895724	PHASE2	UNKNOWN	Hyperbaric Oxygen Therapy to Reduce Lymphedema After Breast Cancer -an Explorative Clinical Trial
NCT03658967	PHASE2	COMPLETED	Clinical Study With Lymfactin® in the Treatment of Patients With Secondary Lymphedema (AdeLE)
NCT03776721	PHASE2	COMPLETED	Treatment of Breast Cancer-related Lymphedema With Stem Cells and Fat Grafting
NCT06494111	PHASE2	RECRUITING	Systemic Therapy of Open-label Prophylactic Pravastatin or Pentoxifylline/Tocopherol Prevention of Lymphedema Advancing to Eventual Fibrosis: an Interventional Registry-embedded Bayesian Randomized Trial for Radiation Sequelae (STOP4-LATE-FIBROSE)