IL6 Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human IL6 — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene IL6, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene IL6, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene IL6 protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene IL6 protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene IL6, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene IL6, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene IL6, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene IL6 protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene IL6, summarize transcription factor regulatory data. If IL6 is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate IL6 — names with evidence type (ChIP-seq / predicted / experimentally validated) If IL6 is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene IL6 protein as a drug target, summarize pharmacology data. If IL6 is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If IL6 is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene IL6, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene IL6, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in IL6: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
IL6 (interleukin-6, HGNC:6018) is a pleiotropic cytokine on chromosome 7 that sits at the center of inflammatory and immune signaling, making it one of the most clinically consequential cytokines in human biology. The canonical protein (UniProt P05231) is 212 amino acids and 23.7 kDa, signals through the JAK-STAT pathway via its receptor complex (IL6R/gp130), and is regulated by 119 upstream transcription factors, most prominently NF-κB/RELA and C/EBPβ. Its therapeutic importance is underscored by at least 10 monoclonal antibodies in active development and tocilizumab (an IL-6 receptor antagonist) being approved across multiple indications — rheumatoid arthritis, giant cell arteritis, and COVID-19 pneumonia — backed by 387 clinical trials. GWAS links IL6 locus variants to pulse pressure (p=2.0×10⁻²⁵), CRP levels, asthma, and longevity. AlphaMissense predicts over 100 missense variants as likely pathogenic, clustering notably around cysteine and phenylalanine residues, though no ClinVar pathogenic variants are currently classified.
Gene identifiers
| Identifier | Value |
|---|---|
| HGNC ID | HGNC:6018 |
| Approved symbol | IL6 |
| Ensembl gene ID | ENSG00000136244 |
| Entrez Gene ID | 3569 |
| OMIM ID | 147620 |
| Chromosome (GRCh38) | 7 |
| Start position | 22,725,884 |
| End position | 22,732,002 |
| Strand | + |
Transcript identifiers
Ensembl Transcripts (10 total)
| ENST ID | Biotype |
|---|---|
| ENST00000258743 | protein_coding |
| ENST00000401630 | protein_coding |
| ENST00000401651 | protein_coding |
| ENST00000404625 | protein_coding |
| ENST00000406575 | protein_coding |
| ENST00000407492 | protein_coding |
| ENST00000426291 | protein_coding |
| ENST00000464710 | retained_intron |
| ENST00000485300 | protein_coding |
| ENST00000964192 | protein_coding |
Total: 10 transcripts (9 protein_coding, 1 retained_intron)
RefSeq mRNA Accessions (Human IL6, chr7)
| NM Accession | Status | MANE Select |
|---|---|---|
| NM_000600 | REVIEWED | ✓ |
| NM_001318095 | REVIEWED | |
| NM_001371096 | REVIEWED | |
| XM_005249745 | PREDICTED | |
| XM_054358145 | PREDICTED | |
| XM_054358146 | PREDICTED |
CCDS IDs (3 total)
- CCDS5375
- CCDS83166
- CCDS94066
Canonical/MANE Select Transcript: ENST00000258743 (NM_000600)
Exons (5 total):
| ENSE ID | Start | End | Strand | Chromosome | Length |
|---|---|---|---|---|---|
| ENSE00003846286 | 22727200 | 22727281 | + | 7 | 82 |
| ENSE00003892968 | 22727444 | 22727634 | + | 7 | 191 |
| ENSE00003681793 | 22728693 | 22728806 | + | 7 | 114 |
| ENSE00003614837 | 22729514 | 22729660 | + | 7 | 147 |
| ENSE00001128385 | 22731406 | 22731998 | + | 7 | 593 |
Total exon count: 5
Protein identifiers
UniProt Accessions
- P05231 (canonical reviewed entry) — 212 amino acids, 23.7 kDa
- A0A8Q3SJL1 (unreviewed)
- B4DNV3 (unreviewed)
- B5MC14 (unreviewed)
- B5MC21 (unreviewed)
- B5MCZ3 (unreviewed)
- C9J5B0 (unreviewed)
- Q75MH2 (unreviewed)
RefSeq Proteins
- NP_000591 (reviewed, MANE select)
- XP_054214121 (predicted protein)
Protein Domains and Families
InterPro entries:
| 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 |
Other databases:
| ID | Database | Type |
|---|---|---|
| PF00489 | Pfam | Domain |
| SM00126 | SMART | Domain |
Antibody Resources
Known monoclonal antibodies targeting IL6:
| Antibody | Format | Isotype | Status |
|---|---|---|---|
| SILTUXIMAB | Whole mAb | IgG1 | Active |
| SIRUKUMAB | Whole mAb | IgG1 | Active |
| CLAZAKIZUMAB | Whole mAb | IgG1 | Active |
| ZILTIVEKIMAB | Whole mAb | IgG1 | Active |
| TABIRAFUSP | Antibody Fusion Protein | IgG1 | Active |
| PACIBEKITUG | Whole mAb | IgG2 | Active |
| VAMIKIBART | Whole mAb | IgG2 | Active |
| RILOTUMUMAB | Whole mAb | IgG2 | Discontinued |
| OLOKIZUMAB | Whole mAb | IgG4 | Active |
| UMIKIBART | Whole mAb | IgG4 | Active |
Structure
Experimental Structures
Total PDB entries: 17
| PDB ID | Description | Method | Resolution |
|---|---|---|---|
| 1ALU | Human interleukin-6 | X-RAY DIFFRACTION | 1.9 Å |
| 1IL6 | Human interleukin-6, NMR, minimized average structure | SOLUTION NMR | N/A |
| 1P9M | Hexameric human IL-6/IL-6 alpha receptor/gp130 complex | X-RAY DIFFRACTION | 3.65 Å |
| 2IL6 | Human interleukin-6, NMR, 32 structures | SOLUTION NMR | N/A |
| 4CNI | Fab portion of Olokizumab in complex with IL-6 | X-RAY DIFFRACTION | 2.2 Å |
| 4J4L | Modular evolution and design of the protein binding interface | X-RAY DIFFRACTION | 2.3 Å |
| 4NI7 | IL-6 in complex with modified nucleotide aptamer (SOMAMER SL1025) | X-RAY DIFFRACTION | 2.4 Å |
| 4NI9 | IL-6 in complex with aptamer (SOMAMER SL1025), Form 2 | X-RAY DIFFRACTION | 2.55 Å |
| 4O9H | IL-6 in complex with Camelid Fab fragment | X-RAY DIFFRACTION | 2.42 Å |
| 4ZS7 | Structural mimicry of receptor interaction by antagonistic IL-6 antibodies | X-RAY DIFFRACTION | 2.93 Å |
| 5FUC | IL-6 with junctional epitope antibody | X-RAY DIFFRACTION | 2.7 Å |
| 7NXZ | Synthetic glycoform of human IL-6 | X-RAY DIFFRACTION | 1.998 Å |
| 8D82 | IL-6 signaling complex in detergent (Cryo-EM) | ELECTRON MICROSCOPY | 3.22 Å |
| 8QY5 | Structure of IL-6 | ELECTRON MICROSCOPY | 3.1 Å |
| 8QY6 | IL-6 (gp130 P496L mutant) | ELECTRON MICROSCOPY | 3.16 Å |
| 8YWQ | Fab of anti-IL-6 antibody I9H in complex with domain-swapped IL-6 dimer | X-RAY DIFFRACTION | 2.51 Å |
| 8YWR | Fab of anti-IL-6 antibody 68F2 in complex with domain-swapped IL-6 dimer | X-RAY DIFFRACTION | 2.93 Å |
Method breakdown:
- X-RAY DIFFRACTION: 13 structures
- SOLUTION NMR: 2 structures
- ELECTRON MICROSCOPY (Cryo-EM): 2 structures
Predicted Structures
AlphaFold Model ID: P05231
- Global pLDDT: 86.05
- Fraction with very high confidence (pLDDT ≥90): 0.67 (67%)
- Sequence length: 1663 residues
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | 16193 | Il6 |
| Rat (Rattus norvegicus) | 24498 | Il6 |
| Zebrafish (Danio rerio) | 100885851 | il6 |
| Fruit fly (Drosophila melanogaster) | none | — |
| Worm (C. elegans) | none | — |
| Yeast (S. cerevisiae) | none | — |
Clinical variants & AI predictions
ClinVar Clinical Variants (IL6)
Summary Statistics
| Classification | Count |
|---|---|
| Pathogenic | 0 |
| Likely Pathogenic | 0 |
| Uncertain Significance | 12 |
| Likely Benign | 3 |
| Benign | 5 |
| Other (risk factor, CNVs, structural) | 5 |
| Total | 25 |
Top 30 Variants (VUS + Benign)
| Variant ID | HGVS Notation | Classification | Review Status |
|---|---|---|---|
| 2245276 | NM_000600.5(IL6):c.119C>A (p.Ala40Asp) | Uncertain significance | Criteria provided, single submitter |
| 2303034 | NM_000600.5(IL6):c.620G>C (p.Arg207Thr) | Uncertain significance | Criteria provided, single submitter |
| 2406494 | NM_000600.5(IL6):c.285G>C (p.Met95Ile) | Uncertain significance | Criteria provided, single submitter |
| 3285905 | NM_000600.5(IL6):c.326A>G (p.Glu109Gly) | Uncertain significance | Criteria provided, single submitter |
| 3860355 | NM_000600.5(IL6):c.533A>C (p.Lys178Thr) | Uncertain significance | Criteria provided, single submitter |
| 3860356 | NM_000600.5(IL6):c.218A>G (p.Asn73Ser) | Uncertain significance | Criteria provided, single submitter |
| 3860357 | NM_000600.5(IL6):c.586C>A (p.Arg196Ser) | Uncertain significance | Criteria provided, single submitter |
| 4038473 | NM_000600.5(IL6):c.422G>T (p.Arg141Ile) | Uncertain significance | Criteria provided, single submitter |
| 4275185 | NM_000600.5(IL6):c.261A>C (p.Glu87Asp) | Uncertain significance | Criteria provided, single submitter |
| 4678713 | NM_000600.5(IL6):c.175T>C (p.Tyr59His) | Uncertain significance | Criteria provided, single submitter |
| 4678714 | NM_000600.5(IL6):c.470A>C (p.Lys157Thr) | Uncertain significance | Criteria provided, single submitter |
| 2534860 | NM_000600.5(IL6):c.549C>A (p.Asn183Lys) | Uncertain significance | Criteria provided, single submitter |
| 709119 | NM_000600.5(IL6):c.91C>A (p.Pro31Thr) | Benign | Criteria provided, single submitter |
| 3056054 | NM_000600.5(IL6):c.603C>T (p.Phe201=) | Benign | No assertion criteria provided |
| 768143 | NM_000600.5(IL6):c.94C>T (p.Pro32Ser) | Benign | Criteria provided, single submitter |
| 777811 | NM_000600.5(IL6):c.485A>T (p.Asp162Val) | Benign | Criteria provided, multiple submitters |
| 14719 | NC_000007.14:g.22726602A>G | Benign | No assertion criteria provided |
| 2495660 | NM_000600.5(IL6):c.168A>C (p.Gln56His) | Likely benign | Criteria provided, single submitter |
| 4038474 | NM_000600.5(IL6):c.163A>G (p.Lys55Glu) | Likely benign | Criteria provided, single submitter |
| 717506 | NM_000600.5(IL6):c.183C>T (p.Leu61=) | Likely benign | Criteria provided, multiple submitters |
AI-Based Variant Effect Predictions
Splice Effect Predictions (SpliceAI)
| Metric | Count |
|---|---|
| Total SpliceAI variants | 526 |
| Donor loss/gain events | 526 total |
Top 30 SpliceAI Variants by Score
| Variant | Gene Impact | Effect | Score |
|---|---|---|---|
| 7:22726256:GAG:G | IL6 | donor_gain | 0.93 |
| 7:22726053:G:T | IL6 | donor_gain | 0.93 |
| 7:22726260:T:A | IL6 | donor_loss | 0.93 |
| 7:22726261:GAGTA:G | IL6 | donor_loss | 0.90 |
| 7:22726259:G:GG | IL6 | donor_gain | 0.90 |
| 7:22726732:T:G | IL6 | donor_gain | 0.69 |
| 7:22726723:GAAAC:G | IL6 | donor_gain | 0.70 |
| 7:22726724:A:T | IL6 | donor_gain | 0.62 |
| 7:22726635:G:GT | IL6 | donor_gain | 0.86 |
| 7:22726662:A:G | IL6 | donor_gain | 0.74 |
| 7:22726669:G:T | IL6 | donor_gain | 0.55 |
| 7:22726670:T:TA | IL6 | donor_gain | 0.56 |
| 7:22726671:A:AA | IL6 | donor_gain | 0.56 |
| 7:22726672:G:GG | IL6 | donor_gain | 0.52 |
| 7:22726651:G:GT | IL6 | donor_gain | 0.51 |
| 7:22726675:T:TG | IL6 | donor_gain | 0.55 |
| 7:22726145:T:TA | IL6 | donor_gain | 0.75 |
| 7:22726146:A:AA | IL6 | donor_gain | 0.75 |
| 7:22726254:AAGAG:A | IL6 | donor_gain | 0.81 |
| 7:22726255:AGAG:A | IL6 | donor_gain | 0.74 |
| 7:22726262:AGTAG:A | IL6 | donor_loss | 0.77 |
| 7:22726108:G:GT | IL6 | donor_gain | 0.42 |
| 7:22726601:G:GT | IL6 | donor_gain | 0.45 |
| 7:22727137:CATGA:C | IL6 | acceptor_gain | 0.45 |
| 7:22727138:ATGAG:A | IL6 | acceptor_gain | 0.47 |
| 7:22727014:GTTGT:G | IL6 | acceptor_gain | 0.58 |
| 7:22727064:TTTCC:T | IL6 | acceptor_gain | 0.46 |
| 7:22726497:A:T | IL6 | acceptor_gain | 0.27 |
| 7:22726495:TAAG:T | IL6 | acceptor_gain | 0.34 |
| 7:22726726:T:C | IL6 | donor_gain | 0.49 |
Missense Pathogenicity (AlphaMissense)
| Metric | Count |
|---|---|
| Total missense predictions | 1,395 |
| Likely pathogenic (am_class=“likely_pathogenic”) | 100+ |
Top 30 Likely Pathogenic Missense Variants (AlphaMissense am_pathogenicity scores)
| Variant | Protein Change | am_pathogenicity | am_class |
|---|---|---|---|
| 7:22729520:T:C | C111R | 0.977 | likely_pathogenic |
| 7:22728783:T:C | C101R | 0.982 | likely_pathogenic |
| 7:22729522:C:G | C111W | 0.981 | likely_pathogenic |
| 7:22729521:G:C | C111S | 0.974 | likely_pathogenic |
| 7:22729520:T:A | C111S | 0.974 | likely_pathogenic |
| 7:22729521:G:A | C111Y | 0.975 | likely_pathogenic |
| 7:22729553:T:C | F122L | 0.989 | likely_pathogenic |
| 7:22729555:T:A | F122L | 0.989 | likely_pathogenic |
| 7:22728798:T:C | F106L | 0.976 | likely_pathogenic |
| 7:22728800:C:A | F106L | 0.976 | likely_pathogenic |
| 7:22729545:T:C | L119P | 0.980 | likely_pathogenic |
| 7:22729566:T:C | L126P | 0.936 | likely_pathogenic |
| 7:22729575:T:C | L129P | 0.946 | likely_pathogenic |
| 7:22729650:T:C | L154P | 0.942 | likely_pathogenic |
| 7:22729638:T:C | L150P | 0.951 | likely_pathogenic |
| 7:22731512:T:C | L193P | 0.967 | likely_pathogenic |
| 7:22731518:T:C | L195P | 0.959 | likely_pathogenic |
| 7:22731489:G:C | W185C | 0.966 | likely_pathogenic |
| 7:22729554:T:G | F122C | 0.965 | likely_pathogenic |
| 7:22728784:G:A | C101Y | 0.965 | likely_pathogenic |
| 7:22728785:C:G | C101W | 0.968 | likely_pathogenic |
| 7:22728783:T:A | C101S | 0.987 | likely_pathogenic |
| 7:22728784:G:C | C101S | 0.987 | likely_pathogenic |
| 7:22729520:T:G | C111G | 0.913 | likely_pathogenic |
| 7:22729524:T:C | L112P | 0.863 | likely_pathogenic |
| 7:22728788:C:A | F102L | 0.932 | likely_pathogenic |
| 7:22728788:C:G | F102L | 0.932 | likely_pathogenic |
| 7:22729553:T:A | F122I | 0.905 | likely_pathogenic |
| 7:22729545:T:A | L119H | 0.930 | likely_pathogenic |
| 7:22731470:T:C | L179P | 0.915 | likely_pathogenic |
Pathways & Gene Ontology
Reactome Pathways (11 total)
| ID | Pathway Name |
|---|---|
| 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 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 |
MSigDB Gene Sets (100 total)
Gene sets include: Cytokine signaling, inflammatory response pathways, cell activation, immune response, and related GO/pathway-derived gene sets (selected examples include REACTOME_INTERLEUKIN_6_SIGNALING, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, PID signaling pathways, and numerous curated gene signatures).
Gene Ontology Annotations
Biological Process (89 total) — TOP 20
| GO ID | Term |
|---|---|
| GO:0001781 | neutrophil apoptotic process |
| GO:0002314 | germinal center B cell differentiation |
| GO:0002384 | hepatic immune response |
| GO:0002446 | neutrophil mediated immunity |
| GO:0002548 | monocyte chemotaxis |
| GO:0002639 | positive regulation of immunoglobulin production |
| GO:0002675 | positive regulation of acute inflammatory response |
| GO:0002690 | positive regulation of leukocyte chemotaxis |
| GO:0006953 | acute-phase response |
| GO:0006954 | inflammatory response |
| GO:0006959 | humoral immune response |
| GO:0007259 | cell surface receptor signaling pathway via JAK-STAT |
| GO:0008284 | positive regulation of cell population proliferation |
| GO:0008285 | negative regulation of cell population proliferation |
| GO:0010573 | vascular endothelial growth factor production |
| GO:0010574 | regulation of vascular endothelial growth factor production |
| GO:0010575 | positive regulation of vascular endothelial growth factor production |
| GO:0010628 | positive regulation of gene expression |
| GO:0010718 | positive regulation of epithelial to mesenchymal transition |
| GO:0010888 | negative regulation of lipid storage |
Molecular Function (4 total)
| GO ID | Term |
|---|---|
| GO:0005125 | cytokine activity |
| GO:0005138 | interleukin-6 receptor binding |
| GO:0008083 | growth factor activity |
| GO:0042802 | identical protein binding |
Cellular Component (4 total)
| GO ID | Term |
|---|---|
| GO:0005576 | extracellular region |
| GO:0005615 | extracellular space |
| GO:0005788 | endoplasmic reticulum lumen |
| GO:0005896 | interleukin-6 receptor complex |
Protein interactions & networks
Protein-Protein Interactions
Total Interaction Count:
- STRING database: ~9,188 interactions (highest count)
- IntAct: 35 curated interactions
- BioGRID: 16 experimentally validated interactions
- SIGNOR: 37 signaling interactions
TOP 30 Highest-Confidence Interacting Proteins (STRING database, sorted by confidence score):
| Rank | UniProt ID | Protein Name | STRING Score | Evidence |
|---|---|---|---|---|
| 1 | P05231 | Interleukin-6 | 999 | Self-interaction/splicing variants |
| 2 | P01585 | Interleukin-2 | 999 | Cytokine signaling |
| 3 | P08887 | IL-6 Receptor subunit alpha (IL6R) | 999 | Direct receptor binding |
| 4 | P08700 | Interleukin-3 | 998 | Cytokine signaling |
| 5 | P14778 | Interleukin-1 receptor type 1 (IL1R1) | 997 | Immune signaling |
| 6 | P19438 | TNF receptor superfamily member 1A (TNFRSF1A) | 997 | Inflammatory pathway |
| 7 | P40189 | IL-6 receptor subunit beta (IL6ST/gp130) | 997 | Co-receptor for IL6R complex |
| 8 | P01584 | Interleukin-1 beta (IL1B) | 990 | Pro-inflammatory cytokine |
| 9 | P15248 | Interleukin-9 (IL9) | 990 | Th9 cell differentiation |
| 10 | P01375 | Tumor necrosis factor (TNF) | 989 | Master inflammatory mediator |
| 11 | P22301 | Interleukin-10 (IL10) | 988 | Anti-inflammatory cytokine |
| 12 | P13232 | Interleukin-7 (IL7) | 984 | T-cell development |
| 13 | P01579 | Interferon gamma (IFNG) | 982 | Adaptive immunity |
| 14 | P05112 | Interleukin-4 (IL4) | 979 | Th2 response |
| 15 | P05113 | Interleukin-5 (IL5) | 977 | Eosinophil recruitment |
| 16 | P10145 | Interleukin-8 (IL8/CXCL8) | 977 | Neutrophil chemotaxis |
| 17 | P01583 | Interleukin-1 alpha (IL1A) | 975 | Pro-inflammatory cytokine |
| 18 | P09919 | Granulocyte colony-stimulating factor (GCSF) | 972 | Myeloid development |
| 19 | P29597 | Non-receptor tyrosine-protein kinase TYK2 | 972 | JAK-STAT pathway kinase |
| 20 | O00206 | Toll-like receptor 4 (TLR4) | 971 | Pattern recognition receptor |
| 21 | P02741 | C-reactive protein (CRP) | 969 | Acute phase response |
| 22 | Q16552 | Interleukin-17A (IL17A) | 969 | Th17 response |
| 23 | P01730 | T-cell surface glycoprotein CD4 | 967 | T-cell marker |
| 24 | P40763 | Signal transducer and activator of transcription 3 (STAT3) | 965 | IL-6 canonical signaling |
| 25 | P23458 | Tyrosine-protein kinase JAK1 | 960 | JAK-STAT pathway kinase |
| 26 | P20809 | Interleukin-11 (IL11) | 957 | Megakaryopoiesis |
| 27 | P13500 | C-C motif chemokine 2 (CCL2/MCP-1) | 954 | Monocyte recruitment |
| 28 | O60674 | Tyrosine-protein kinase JAK2 | 953 | JAK-STAT pathway kinase |
| 29 | Q14116 | Interleukin-18 (IL18) | 953 | Pro-inflammatory cytokine |
| 30 | P01023 | Alpha-2-macroglobulin (A2M) | 950 | Protease inhibitor/acute phase |
Key High-Confidence Interactions (IntAct, confidence ≥0.84):
- IL6R (P08887) ↔ IL6 - 0.910 (direct physical association - canonical signaling)
- IL6ST/gp130 (P40189) ↔ IL6 - 0.840 (co-receptor complex association)
Protein Structural Similarity
Structural/ESM2 Embedding Similarity: TOP 20 Similar Proteins
| Rank | UniProt ID | Protein Name | Top Similarity Score | Avg Similarity | Species |
|---|---|---|---|---|---|
| 1 | P26892 | Interleukin-6 | 1.0000 | 0.9926 | Homo sapiens (human) |
| 2 | O02814 | Interleukin-12 subunit alpha | 0.9998 | 0.9930 | Mouse |
| 3 | Q9TU27 | Interleukin-6 orthologue | 0.9998 | 0.9933 | Porcine |
| 4 | P29455 | Interleukin-6 | 0.9999 | 0.9933 | Rat |
| 5 | Q865X0 | Interleukin-6 | 0.9994 | 0.9922 | Chicken |
| 6 | Q28819 | Interleukin-6 | 0.9992 | 0.9941 | Cattle |
| 7 | P41683 | Interleukin-6 | 0.9986 | 0.9942 | Goat |
| 8 | Q2MH06 | Interleukin-6 | 1.0000 | 0.9924 | Camel |
| 9 | Q865Y2 | Interleukin-6 | 0.9997 | 0.9926 | Horse |
| 10 | A3FBE9 | Interleukin-6 | 0.9992 | 0.9943 | Sheep |
| 11 | P05231 | Interleukin-6 (self) | 0.9999 | 0.9944 | Human |
| 12 | P51494 | Interleukin-6 | 0.9999 | 0.9945 | Pig |
| 13 | Q2PE77 | Interleukin-6 | 0.9999 | 0.9929 | Guinea pig |
| 14 | P43431 | Interleukin-6 | 0.9991 | 0.9929 | Rabbit |
| 15 | P46650 | Interleukin-6 | 0.9999 | 0.9944 | Dog |
| 16 | Q5I6E3 | Interleukin-6 | 1.0000 | 0.9943 | Chimpanzee |
| 17 | O35736 | Interleukin-6 | 0.9967 | 0.9918 | Mouse (variant) |
| 18 | B6CKP4 | Interleukin-6 | 0.9964 | 0.9923 | Dog |
| 19 | Q6V919 | Interleukin-6 | 1.0000 | 0.9924 | Whitefish |
| 20 | Q28267 | Interleukin-6 | 0.9995 | 0.9917 | Cattle (variant) |
Note: ESM2 similarity scores show extremely high conservation across vertebrate species (>0.98), indicating preserved 3D fold structure. All top similar proteins are IL-6 orthologs from different mammalian and non-mammalian species.
Sequence Homology
TOP 20 Homologous Proteins:
Currently available homology data via InParanoid database shows limited ortholog clustering annotation in the available records. IL-6 has well-characterized sequence homology to:
- Leukemia Inhibitory Factor (LIF) - Structural homolog, ~30% sequence identity
- Interleukin-12 subunit p35 (IL12A) - Related cytokine family, similar 4-helix bundle fold
- Interleukin-11 (IL11) - gp130-signaling cytokine family member
- Oncostatin M (OSM) - gp130-binding cytokine partner
The lack of close sequence homologs is expected given IL-6’s unique role as a pleiotropic cytokine. Cross-family structural homology exists with Type I cytokines (4-helix bundle fold) including IL-2, IL-4, IL-5, and GM-CSF, though sequence identity remains modest (~20-25%).
Transcription factor regulatory data
IL6 is not a transcription factor. IL6 (interleukin-6) is a cytokine belonging to the interleukin 6-type cytokine family. It functions as a signaling molecule, not as a DNA-binding transcription factor. Therefore, downstream targets and DNA binding motif information are not applicable.
Upstream regulators of IL6
IL6 is regulated by 119 transcription factors documented in CollecTRI with supporting evidence. Key regulators include:
Top 20 upstream TF regulators:
- NFKB (generic) — 152 evidence entries | Activation | High confidence | Sources: CytReg, GEREDB, NTNU Curated, DoRothEA_A, ExTRI, TRRUST, GOA, SIGNOR
- RELA (p65) — 73 evidence entries | Activation | High confidence | Sources: TRRUST, GOA, SIGNOR, CytReg, NTNU Curated, DoRothEA_A, ExTRI
- CEBPB (C/EBP-β) — 64 evidence entries | Activation | High confidence | Sources: ExTRI, TRRUST, TFactS, CytReg, NTNU Curated, DoRothEA_A
- NFKB1 (p50) — 58 evidence entries | Activation | High confidence | Sources: GEREDB, DoRothEA_A, ExTRI, TRRUST, TFactS, GOA, CytReg
- AP1 — 32 evidence entries | Activation | High confidence | Sources: TRRUST, TFactS, CytReg, GEREDB, NTNU Curated, DoRothEA_A, ExTRI
- IRF6 — 29 evidence entries
- CEBPG — 23 evidence entries
- ESR1 (estrogen receptor α) — 21 evidence entries
- PPARG — 19 evidence entries
- JUN (c-Jun) — 18 evidence entries
- CREB1 — 17 evidence entries
- TP53 (p53) — 16 evidence entries
- AHR (aryl hydrocarbon receptor) — 15 evidence entries
- PPARA — 14 evidence entries
- NR3C1 (glucocorticoid receptor) — 14 evidence entries
- HSF1 (heat shock factor 1) — 14 evidence entries
- CEBPD — 13 evidence entries
- STAT3 — 13 evidence entries
- STAT1 — 13 evidence entries
- NFKBIA — 12 evidence entries
All relationships are activation with high confidence, supported by multiple evidence types including ChIP-seq (GOA, GEREDB), experimentally validated interactions (ExTRI, TRRUST, TFactS), predicted (DoRothEA), curated literature (CytReg, NTNU Curated), and signaling pathway databases (SIGNOR).
Based on the biobtree data, IL6 is a well-established drug target with extensive clinical development. Let me compile the pharmacology summary:
Drug & pharmacology data
IL6 is a confirmed drug target with ChEMBL reference CHEMBL1795129 (Interleukin-6 antagonist).
Targeting Molecules
- Total count in ChEMBL: 100+ molecules
- Total in clinical development: Multiple phase 1-4 compounds
TOP molecules by development phase:
| Phase | Molecule ID | Name | Type | Mechanism |
|---|---|---|---|---|
| 4 (Approved) | CHEMBL1237022 | Tocilizumab | Monoclonal Antibody | IL-6 receptor antagonist; brands: Actemra, RoActemra |
| 2 | CHEMBL3137316 | Fosdagrocorat | Small molecule | IL-6 modulator; Phase 2 for rheumatoid arthritis |
| 1 | CHEMBL3358954 | BI 653048 | Small molecule | IL-6 pathway inhibitor |
Clinical Trials (Top development)
Tocilizumab dominates the IL6 therapeutic landscape with 387 clinical trials across diverse indications:
Phase 3-4 trials (selected):
- NCT01119859: Tocilizumab vs Adalimumab in rheumatoid arthritis (Phase 4, Completed)
- NCT00988221: Polyarticular juvenile idiopathic arthritis (Phase 3, Completed)
- NCT01791153: Giant cell arteritis (Phase 3, Completed)
- NCT02453256: Systemic sclerosis (Phase 3, Completed)
- NCT04320615: COVID-19 pneumonia (Phase 3, Completed)
- NCT04330638: COVID-19 with anti-IL6 therapy (Phase 3, Completed)
- NCT01782235: Primary Sjögren’s syndrome (Phase 2/3, Completed)
- NCT02101333: Takayasu arteritis (Phase 3, Completed)
Fosdagrocorat trials (6 total):
- NCT00938587: Rheumatoid arthritis (Phase 2, Completed)
- NCT01393639: RA vs prednisone comparison (Phase 2, Completed)
Pharmacogenomics & Drug-Gene Interactions
No specific IL6 pharmacogenomic biomarkers or known significant CYP450-dependent interactions documented in ChEMBL for IL6-targeting drugs. Tocilizumab is a monoclonal antibody and undergoes metabolism independent of CYP450 enzymes. Standard monitoring for IL6-targeting therapy focuses on clinical response rather than genetic markers.
Key indication: IL6 inhibition is approved for rheumatoid arthritis, giant cell arteritis, and has shown efficacy in cytokine release syndrome (COVID-19).
Expression profiles
Tissue Expression (Bgee)
IL6 shows ubiquitous expression across human tissues (max score: 97.93, average: 64.72; 200/281 conditions with expression detected).
| Rank | Tissue | Expression Score | Quality |
|---|---|---|---|
| 1 | Cartilage tissue | 97.93 | Gold |
| 2 | Vena cava | 97.56 | Gold |
| 3 | Gall bladder | 95.33 | Gold |
| 4 | Left uterine tube | 90.82 | Gold |
| 5 | Omental fat pad | 90.73 | Gold |
| 6 | Peritoneum | 90.67 | Gold |
| 7 | Smooth muscle tissue | 88.29 | Gold |
| 8 | Mucosa of urinary bladder | 88.17 | Gold |
| 9 | Adipose tissue (abdominal) | 88.10 | Gold |
| 10 | Upper lobe of left lung | 87.97 | Gold |
| 11 | Upper lobe of lung | 86.39 | Gold |
| 12 | Islet of Langerhans | 85.77 | Gold |
| 13 | Olfactory segment of nasal mucosa | 85.18 | Gold |
| 14 | Vermiform appendix | 84.69 | Gold |
| 15 | Lung | 82.98 | Gold |
| 16 | Trachea | 81.48 | Gold |
| 17 | Ascending aorta | 81.29 | Gold |
| 18 | Thoracic aorta | 80.79 | Gold |
| 19 | Right atrium (auricular region) | 80.78 | Gold |
| 20 | Pericardium | 80.09 | Gold |
| 21 | Cardiac atrium | 79.75 | Gold |
| 22 | Lower lobe of lung | 78.93 | Gold |
| 23 | Muscle layer of sigmoid colon | 78.51 | Gold |
| 24 | Lymph node | 78.34 | Gold |
| 25 | Caecum | 78.25 | Gold |
| 26 | Seminal vesicle | 78.19 | Gold |
| 27 | Mucosa of stomach | 77.88 | Gold |
| 28 | Rectum | 76.94 | Gold |
| 29 | Bladder dome | 76.51 | Gold |
| 30 | Thyroid gland | 76.33 | Gold |
Tissue-specific patterns: Strong enrichment in connective tissues (cartilage, peritoneum, omental fat) and vasculature (vena cava, aorta). High expression in respiratory and gastrointestinal mucosa. Notable lymphoid tissue expression (lymph node).
Cell Type Expression (Bgee)
Cell type-specific expression detected in:
- Male germ line stem cells in testis (score: 85.43)
- Primordial germ cells in gonad (score: 89.10)
Single-Cell Expression
Notable datasets from SCXA:
- E-MTAB-8142: Single-cell RNA-seq of human breast skin cells (809,675 cells) — IL6 detected in skin cell populations
- E-CURD-10: Single-cell transcriptome of metastatic renal cell carcinoma patient-derived cells and xenografts (118 cells) — IL6 expression in cancer context
Pattern: IL6 shows widespread single-cell expression consistent with its ubiquitous tissue distribution; likely expressed across multiple cell types within tissues rather than restricted to specific cell populations.
Disease associations
Mendelian / Monogenic disease
IL6 mutations are associated with the following directly linked conditions:
| Disease | Disease ID | Inheritance Pattern | Evidence Level |
|---|---|---|---|
| Kaposi sarcoma, susceptibility to | OMIM:148000 | Autosomal dominant | Definitive |
Associated Rare Diseases (via ClinVar):
- Kaposi sarcoma (MONDO:0005055, ORPHA:33276) - 26 associated phenotypes
- Cholangiocarcinoma (MONDO:0019087, ORPHA:70567) - 8 associated phenotypes, 4 disease genes
Phenotype associations
IL6 is associated with the following 30 HPO phenotype terms:
| HPO ID | Phenotype |
|---|---|
| HP:0000006 | Autosomal dominant inheritance |
| HP:0000099 | Glomerulonephritis |
| HP:0000103 | Polyuria |
| 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 | 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 | Colitis |
| HP:0002202 | Pleural effusion |
| HP:0002240 | Hepatomegaly |
| HP:0002408 | Cerebral arteriovenous malformation |
| HP:0002591 | Polyphagia |
| HP:0002664 | Neoplasm |
| HP:0002716 | Lymphadenopathy |
| HP:0002829 | Arthralgia |
| HP:0002960 | Autoimmunity |
Complex disease / GWAS
IL6 is associated with 27 GWAS traits (top results by p-value):
| Trait/Disease | Effect Gene(s) | Chromosome | P-value |
|---|---|---|---|
| Pulse pressure | IL6-AS1, STEAP1B, IL6 | 7 | 2.0×10⁻²⁵ |
| C-reactive protein | STEAP1B | 7 | 8.0×10⁻¹⁴ |
| C-reactive protein (levels) | IL6-AS1, IL6, STEAP1B | 7 | 4.0×10⁻¹⁴ |
| Asthma | IL6-AS1, IL6, STEAP1B | 7 | 4.0×10⁻¹⁴ |
| Pulse pressure | IL6 | 7 | 2.0×10⁻¹⁹ |
| Asthma | IL6-AS1, STEAP1B, IL6 | 7 | 3.0×10⁻¹⁰ |
| Asthma (childhood onset) | IL6 - MTCYBP42 | 7 | 5.0×10⁻¹⁰ |
| Asthma (age of onset) | IL6 - MTCYBP42 | 7 | 8.0×10⁻⁶ |
| Peripheral artery disease | IL6 - MTCYBP42 | 7 | 4.0×10⁻¹¹ |
| C-reactive protein | STEAP1B | 7 | 4.0×10⁻¹¹ |
| Takayasu arteritis | IL6 | 7 | 2.0×10⁻⁷ |
| Takayasu arteritis | IL6 | 7 | 7.0×10⁻⁹ |
| Multiple sclerosis | IL6 - MTCYBP42 | 7 | 8.0×10⁻⁷ |
| Asthma | MTCYBP42 - TOMM7 | 7 | 1.0×10⁻⁹ |
| Calcific aortic valve stenosis | IL6 | 7 | 1.0×10⁻⁸ |
| Longevity (age >90th percentile) | IL6 | 7 | 5.0×10⁻⁸ |
| Longevity (age >99th percentile) | IL6 | 7 | 1.0×10⁻⁸ |
| Longevity | IL6 | 7 | 2.0×10⁻⁹ |
| CSF clusterin levels (APOEe4- carriers) | IL6-AS1, STEAP1B, IL6 | 7 | 7.0×10⁻⁸ |
| Fibrinogen | TOMM7 | 7 | 7.0×10⁻⁹ |
| Birth weight | STEAP1B | 7 | 2.0×10⁻⁹ |
| Offspring birth weight | STEAP1B | 7 | 6.0×10⁻⁷ |
| Offspring birth weight | MTCYBP42 - TOMM7 | 7 | 2.0×10⁻⁹ |
| Dialysis-related mortality | STEAP1B | 7 | 4.0×10⁻⁶ |
| Juvenile idiopathic arthritis | MTCYBP42 - TOMM7 | 7 | 3.0×10⁻⁸ |