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Reviewed, UniProtKB/Swiss-Prot P05231 (IL6_HUMAN)

Last modified February 9, 2010. Version 131. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Interleukin-6
      Short name=IL-6
Alternative name(s):
    B-cell stimulatory factor 2
      Short name=BSF-2
    Interferon beta-2
      Short name=IFN-beta-2
    Hybridoma growth factor
    CTL differentiation factor
      Short name=CDF
Gene names
Name: IL6
Synonyms: IFNB2
OrganismHomo sapiens (Human) [Complete proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length212 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response. Plays an essential role in the final differentiation of B-cells into Ig-secreting cells Involved in lymphocyte and monocyte differentiation. It induces myeloma and plasmacytoma growth and induces nerve cells differentiation Acts on B-cells, T-cells, hepatocytes, hematopoeitic progenitor cells and cells of the CNS. Also acts as a myokine. It is discharged into the bloodstream after muscle contraction and acts to increase the breakdown of fats and to improve insulin resistance.

Subcellular location

Secreted.

Post-translational modification

N- and O-glycosylated. Ref.14

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, disrutption 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.

Involvement in disease

Genetic variations in IL6 are associated with susceptibility to systemic juvenile rheumatoid arthritis [MIM:604302]. Systemic juvenile rheumatoid arthritis is juvenile chronic arthritis associated with severe, debilitating, extraarticular features, and occasionally fatal complications. Despite medical treatment, many children still experience early joint destruction, necessitating surgical replacement.

At least 1 polymorphism in the IL6 gene renders HIV-infected men susceptible to Kaposi sarcoma [MIM:148000]. Kaposi sarcoma is a sarcoma of spindle cells mixed with angiomatous tissue. A relatively rare malignant skin tumor that results in multifocal purplish colored papules or plaques that eventually form nodules. Most commonly seen in patients who suffer from AIDS.

Sequence similarities

Belongs to the IL-6 superfamily.

Ontologies

Keywords
   Biological processAcute phase
   Cellular componentSecreted
   Coding sequence diversityPolymorphism
   DomainSignal
   Molecular functionCytokine
Growth factor
   PTMDisulfide bond
Glycoprotein
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Gene Ontology (GO)
   Biological processacute-phase response

Traceable author statement. Source: UniProtKB

defense response to Gram-negative bacterium

Inferred from expression pattern. Source: UniProtKB

defense response to Gram-positive bacterium

Inferred from expression pattern. Source: UniProtKB

defense response to virus Ref.4

Inferred from direct assay. Source: UniProtKB

endocrine pancreas development

Inferred from sequence or structural similarity. Source: UniProtKB

glucagon secretion

Inferred from sequence or structural similarity. Source: UniProtKB

hepatic immune response

Inferred from direct assay. Source: UniProtKB

humoral immune response Ref.1

Inferred by curator. Source: UniProtKB

interleukin-6-mediated signaling pathway

Inferred from direct assay. Source: UniProtKB

monocyte chemotaxis

Inferred by curator. Source: UniProtKB

negative regulation of apoptosis

Inferred from direct assay. Source: UniProtKB

negative regulation of cell proliferation Ref.4

Traceable author statement. Source: ProtInc

negative regulation of chemokine biosynthetic process

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of collagen biosynthetic process

Inferred from direct assay. Source: UniProtKB

neuron projection development

Inferred from mutant phenotype. Source: UniProtKB

neutrophil apoptosis

Inferred from direct assay. Source: UniProtKB

neutrophil mediated immunity

Inferred by curator. Source: UniProtKB

platelet activation

Traceable author statement. Source: UniProtKB

positive regulation of B cell activation Ref.1

Inferred from direct assay. Source: UniProtKB

positive regulation of MAPKKK cascade

Inferred from direct assay. Source: UniProtKB

positive regulation of T cell proliferation

Inferred from direct assay. Source: UniProtKB

positive regulation of acute inflammatory response

Inferred from direct assay. Source: UniProtKB

positive regulation of anti-apoptosis

Inferred from mutant phenotype. Source: UniProtKB

positive regulation of chemokine production

Inferred from direct assay. Source: UniProtKB

positive regulation of gene-specific transcription

Inferred from direct assay. Source: UniProtKB

positive regulation of immunoglobulin secretion Ref.1

Inferred from direct assay. Source: UniProtKB

positive regulation of interleukin-6 production

Inferred from direct assay. Source: UniProtKB

positive regulation of leukocyte chemotaxis

Inferred by curator. Source: UniProtKB

positive regulation of osteoblast differentiation

Traceable author statement. Source: UniProtKB

positive regulation of peptidyl-serine phosphorylation

Inferred from direct assay. Source: MGI

positive regulation of smooth muscle cell proliferation

Inferred from direct assay. Source: UniProtKB

positive regulation of transcription factor activity

Inferred from direct assay. Source: UniProtKB

positive regulation of transcription from RNA polymerase II promoter

Inferred from direct assay. Source: MGI

positive regulation of translation

Inferred from direct assay. Source: UniProtKB

positive regulation of tyrosine phosphorylation of Stat3 protein

Inferred from direct assay. Source: UniProtKB

regulation of angiogenesis

Inferred by curator. Source: UniProtKB

regulation of vascular endothelial growth factor production

Inferred from direct assay. Source: UniProtKB

response to glucocorticoid stimulus

Inferred from direct assay. Source: UniProtKB

response to peptidoglycan

Inferred from expression pattern. Source: UniProtKB

   Cellular componentextracellular space Ref.4

Inferred from direct assay. Source: UniProtKB

interleukin-6 receptor complex

Inferred from direct assay. Source: UniProtKB

   Molecular functioncytokine activity Ref.1 Ref.4

Inferred from direct assay. Source: UniProtKB

growth factor activity

Inferred from direct assay. Source: UniProtKB

interleukin-6 receptor binding Ref.14

Non-traceable author statement. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2929 Ref.14 Ref.12 Ref.13
Chain30 – 212183Interleukin-6
PRO_0000015582

Amino acid modifications

Glycosylation731N-linked (GlcNAc...)
Disulfide bond72 ↔ 78 Ref.15 Ref.16
Disulfide bond101 ↔ 111 Ref.15 Ref.16

Natural variations

Natural variant321P → S: dbSNP rs2069830. Ref.10
VAR_013075
Natural variant1621D → E: dbSNP rs13306435.
VAR_029266
Natural variant1621D → V: dbSNP rs2069860. Ref.10
VAR_013076

Experimental info

Mutagenesis1731A → V: Almost no loss of activity.
Mutagenesis1851W → R: No loss of activity.
Mutagenesis2041S → P: 87% loss of activity.
Mutagenesis2101R → K, E, Q, T, A or P: Loss of activity.
Mutagenesis2121M → T, N, S or R: Loss of activity.

Secondary structure

............... 212
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P05231-1 [UniParc].

Last modified August 13, 1987. Version 1.
Checksum: 1F1ED1FE1B734079

FASTA21223,718
        10         20         30         40         50         60 
MNSFSTSAFG PVAFSLGLLL VLPAAFPAPV PPGEDSKDVA APHRQPLTSS ERIDKQIRYI 

        70         80         90        100        110        120 
LDGISALRKE TCNKSNMCES SKEALAENNL NLPKMAEKDG CFQSGFNEET CLVKIITGLL 

       130        140        150        160        170        180 
EFEVYLEYLQ NRFESSEEQA RAVQMSTKVL IQFLQKKAKN LDAITTPDPT TNASLLTKLQ 

       190        200        210 
AQNQWLQDMT THLILRSFKE FLQSSLRALR QM 

« Hide

References

« Hide 'large scale' references
[1]"Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin."
Hirano T., Yasukawa K., Harada H., Taga T., Watanabe Y., Matsuda T., Kashiwamura S., Nakajima K., Koyama K., Iwamatsu A., Tsunasawa S., Sakiyama F., Matsui H., Takahara Y., Taniguchi T., Kishimoto T.
Nature 324:73-76(1986) [PubMed: 3491322] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], PARTIAL PROTEIN SEQUENCE.
[2]"Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene."
Yasukawa K., Hirano T., Watanabe Y., Muratani K., Matsuda T., Nakai S., Kishimoto T.
EMBO J. 6:2939-2945(1987) [PubMed: 3500852] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]"Anti-beta-interferon antibodies inhibit the increased expression of HLA-B7 mRNA in tumor necrosis factor-treated human fibroblasts: structural studies of the beta 2 interferon involved."
May L.T., Helfgott D.C., Sehgal P.B.
Proc. Natl. Acad. Sci. U.S.A. 83:8957-8961(1986) [PubMed: 3538015] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]"Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines."
Zilberstein A., Ruggieri R., Korn J.H., Revel M.
EMBO J. 5:2529-2537(1986) [PubMed: 3023045] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]"Molecular cloning and expression of hybridoma growth factor in Escherichia coli."
Brakenhoff J.P.J., de Groot E.R., Evers R.F., Pannekoek H., Aarden L.A.
J. Immunol. 139:4116-4121(1987) [PubMed: 3320204] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[6]"Deletion of 3' untranslated region of human BSF-2 mRNA causes stabilization of the mRNA and high-level expression in mouse NIH3T3 cells."
Tonouchi N., Miwa K., Karasuyama H., Matsui H.
Biochem. Biophys. Res. Commun. 163:1056-1062(1989) [PubMed: 2789513] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[7]"Structural analysis of the sequence coding for an inducible 26-kDa protein in human fibroblasts."
Haegeman G., Content J., Volckaert G., Derynck R., Tavernier J., Fiers W.
Eur. J. Biochem. 159:625-632(1986) [PubMed: 3758081] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
Tissue: Fibroblast.
[8]"Interleukin 6: identification as a hematopoietic colony-stimulating factor."
Wong G., Witek-Giannotti J., Hewick R., Clark S., Ogawa M.
Behring Inst. Mitt. 83:40-47(1988) [PubMed: 3266463] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[9]"Stable and efficient expression of human interleukin-6 cDNA in mammalian cells after gene transfer."
Chen Q.Y.
Zhonghua Zhong Liu Za Zhi 14:340-344(1992) [PubMed: 1291290] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[10]SeattleSNPs variation discovery resource
Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS SER-32 AND VAL-162.
[11]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Lung.
[12]"Separation and comparison of two monokines with lymphocyte-activating factor activity: IL-1 beta and hybridoma growth factor (HGF). Identification of leukocyte-derived HGF as IL-6."
van Damme J., van Beeumen J., Decock B., van Snick J., de Ley M., Billiau A.
J. Immunol. 140:1534-1541(1988) [PubMed: 3279116] [Abstract]
Cited for: PROTEIN SEQUENCE OF 30-63.
[13]"Interleukin 6 is the principal cytolytic T lymphocyte differentiation factor for thymocytes in human leukocyte conditioned medium."
Ming J.E., Cernetti C., Steinman R.M., Granelli-Piperno A.
J. Mol. Cell. Immunol. 4:203-211(1989) [PubMed: 2610854] [Abstract]
Cited for: PROTEIN SEQUENCE OF 30-50.
[14]"Marked cell-type-specific differences in glycosylation of human interleukin-6."
May L.T., Shaw J.E., Khanna A.K., Zabriskie J.B., Sehgal P.B.
Cytokine 3:204-211(1991) [PubMed: 1883960] [Abstract]
Cited for: PROTEIN SEQUENCE OF 30-40, GLYCOSYLATION.
[15]"Structure, stability and biological properties of a N-terminally truncated form of recombinant human interleukin-6 containing a single disulfide bond."
Breton J., la Fiura A., Bertolero F., Orsini G., Valsasina B., Ziliotto R., de Filippis V., Polverino de Laureto P., Fontana A.
Eur. J. Biochem. 227:573-581(1995) [PubMed: 7851440] [Abstract]
Cited for: PROTEIN SEQUENCE OF 50-212 OF RECOMBINANT FORM LACKING FIRST DISULFIDE BOND.
[16]"Disulfide structures of human interleukin-6 are similar to those of human granulocyte colony stimulating factor."
Clogston C.L., Boone T.C., Crandall B.C., Mendiaz E.A., Lu H.S.
Arch. Biochem. Biophys. 272:144-151(1989) [PubMed: 2472117] [Abstract]
Cited for: DISULFIDE BONDS.
[17]"Evidence for the importance of a positive charge and an alpha-helical structure of the C-terminus for biological activity of human IL-6."
Luetticken C., Kruettgen A., Moeller C., Heinrich P.C., Rose-John S.
FEBS Lett. 282:265-267(1991) [PubMed: 2037043] [Abstract]
Cited for: MUTAGENESIS.
[18]"Folding topologies of human interleukin-6 and its mutants as studied by NMR spectroscopy."
Nishimura C., Watanabe A., Gouda H., Shimada I., Arata Y.
Biochemistry 35:273-281(1996) [PubMed: 8555185] [Abstract]
Cited for: STRUCTURE BY NMR.
[19]"Solution structure of recombinant human interleukin-6."
Xu G.-Y., Yu H.-A., Hong J., Stahl M., McDonagh T., Kay L.E., Cumming D.A.
J. Mol. Biol. 268:468-481(1997) [PubMed: 9159484] [Abstract]
Cited for: STRUCTURE BY NMR.
[20]"1.9-A crystal structure of interleukin 6: implications for a novel mode of receptor dimerization and signaling."
Somers W., Stahl M., Seehra J.S.
EMBO J. 16:989-997(1997) [PubMed: 9118960] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS).
[21]"The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis."
Fishman D., Faulds G., Jeffery R., Mohamed-Ali V., Yudkin J.S., Humphries S., Woo P.
J. Clin. Invest. 102:1369-1376(1998) [PubMed: 9769329] [Abstract]
Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO SYSTEMIC JUVENILE RHEUMATOID ARTHRITIS.
[22]"An IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in men infected with human immunodeficiency virus."
Foster C.B., Lehrnbecher T., Samuels S., Stein S., Mol F., Metcalf J.A., Wyvill K., Steinberg S.M., Kovacs J., Blauvelt A., Yarchoan R., Chanock S.J.
Blood 96:2562-2567(2000) [PubMed: 11001912] [Abstract]
Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO KAPOSI SARCOMA.
[23]"A nucleotide variant in the promoter region of the interleukin-6 gene associated with decreased bone mineral density."
Ota N., Nakajima T., Nakazawa I., Suzuki T., Hosoi T., Orimo H., Inoue S., Shirai Y., Emi M.
J. Hum. Genet. 46:267-272(2001) [PubMed: 11355017] [Abstract]
Cited for: INVOLVEMENT IN BMD.
[24]"Association of interleukin-6 promoter variant with bone mineral density in pre-menopausal women."
Chung H.W., Seo J.-S., Hur S.E., Kim H.L., Kim J.Y., Jung J.H., Kim L.H., Park B.L., Shin H.D.
J. Hum. Genet. 48:243-248(2003) [PubMed: 12768442] [Abstract]
Cited for: INVOLVEMENT IN BMD.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
X04430 mRNA. Translation: CAA28026.1.
M14584 mRNA. Translation: AAA52728.1.
X04602 mRNA. Translation: CAA28268.1.
Y00081 Genomic DNA. Translation: CAA68278.1.
M18403 mRNA. Translation: AAA52729.1.
M29150 mRNA. Translation: AAA59154.1.
X04402 Genomic DNA. Translation: CAA27990.1.
X04403 mRNA. Translation: CAA27991.1.
M54894 mRNA. Translation: AAC41704.1.
S56892 mRNA. Translation: AAD13886.1.
AF372214 Genomic DNA. Translation: AAK48987.1.
BC015511 mRNA. Translation: AAH15511.1.
IPIIPI00007793.
PIRIVHUB2. A32648.
RefSeqNP_000591.1.
UniGeneHs.654458

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1ALUX-ray1.90A28-212[»]
1IL6NMR-A28-212[»]
1N2Qmodel-E/F30-212[»]
1P9MX-ray3.65B29-212[»]
2IL6NMR-A28-212[»]
ModBaseSearch...

Protein-protein interaction databases

DIPDIP-482N.
IntActP05231. 4 interactions.
STRINGP05231.

Proteomic databases

PRIDEP05231.

Genome annotation databases

EnsemblENST00000258743; ENSP00000258743; ENSG00000136244; Homo sapiens. [Genome view]
ENST00000404625; ENSP00000385675; ENSG00000136244; Homo sapiens. [Genome view]
GeneID3569.
KEGGhsa:3569.
UCSCuc003svj.2. human.

Organism-specific databases

CTD3569.
GeneCardsGC07P022732.
H-InvDBHIX0006514.
HGNCHGNC:6018. IL6.
HPACAB023406.
MIM147620. gene.
148000. phenotype.
604302. phenotype.
Orphanet92. Juvenile Idiopathic Arthritis.
PharmGKBPA198.
GenAtlasSearch...

Phylogenomic databases

eggNOGprNOG13272.
HOVERGENP05231.
InParanoidP05231.
OMALQFSLRA.
OrthoDBEOG9H48PT.
PhylomeDBP05231.

Enzyme and pathway databases

Pathway_Interaction_DBamb2_neutrophils_pathway. amb2 Integrin signaling.
faspathway. FAS signaling pathway (CD95).
il23pathway. IL23-mediated signaling events.
il27pathway. IL27-mediated signaling events.
il6_7pathway. IL6-mediated signaling events.
lysophospholipid_pathway. LPA receptor mediated events.

Gene expression databases

ArrayExpressP05231.
BgeeP05231.
CleanExHS_IL6.
GenevestigatorP05231.
GermOnlineENSG00000136244. Homo sapiens.

Family and domain databases

InterProIPR009079. 4_helix_cytokine-like_core.
IPR003573. IL6_MGF_GCSF.
IPR003574. Interleukin_6.
[Graphical view]
PANTHERPTHR11457. Interleukin_6. 1 hit.
PfamPF00489. IL6. 1 hit.
[Graphical view]
PIRSFPIRSF001935. IL6_MGF_GCSF. 1 hit.
PRINTSPR00433. IL6GCSFMGF.
PR00434. INTERLEUKIN6.
SMARTSM00126. IL6. 1 hit.
[Graphical view]
PROSITEPS00254. INTERLEUKIN_6. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

DrugBankDB01169. Arsenic trioxide.
DB01128. Bicalutamide.
DB01404. Ginseng.
DB00641. Simvastatin.
NextBio13950.
PMAP-CutDBP05231.
SOURCESearch...

Entry information

Entry nameIL6_HUMAN
AccessionPrimary (citable) accession number: P05231
Secondary accession number(s): Q9UCU2, Q9UCU3, Q9UCU4
Entry history
Integrated into UniProtKB/Swiss-Prot: August 13, 1987
Last sequence update: August 13, 1987
Last modified: February 9, 2010
This is version 131 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

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Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents