Reviewed, UniProtKB/Swiss-Prot P05231 (IL6_HUMAN)

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	212 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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 process	Acute phase
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Domain	Signal
Molecular function	Cytokine Growth factor
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing
Gene Ontology (GO)
Biological process	acute-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 component	extracellular space Ref.4 Inferred from direct assay. Source: UniProtKB interleukin-6 receptor complex Inferred from direct assay. Source: UniProtKB
Molecular function	cytokine 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 29

29

Ref.14 Ref.12 Ref.13

Chain

30 – 212

183

Interleukin-6

PRO_0000015582

Amino acid modifications

Glycosylation

73

1

N-linked (GlcNAc...)

Disulfide bond

72 ↔ 78

Ref.15 Ref.16

Disulfide bond

101 ↔ 111

Ref.15 Ref.16

Natural variations

Natural variant

32

1

P → S: dbSNP rs2069830. Ref.10

VAR_013075

Natural variant

162

1

D → E: dbSNP rs13306435.

VAR_029266

Natural variant

162

1

D → V: dbSNP rs2069860. Ref.10

VAR_013076

Experimental info

Mutagenesis

173

1

A → V: Almost no loss of activity.

Mutagenesis

185

1

W → R: No loss of activity.

Mutagenesis

204

1

S → P: 87% loss of activity.

Mutagenesis

210

1

R → K, E, Q, T, A or P: Loss of activity.

Mutagenesis

212

1

M → T, N, S or R: Loss of activity.

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

212

Helix Strand Turn

Details...

Helix

49 – 75

27

Helix

97 – 99

3

Helix

108 – 132

25

Helix

137 – 157

21

Beta strand

159 – 161

3

Helix

169 – 180

12

Helix

184 – 209

26

Sequences

	Sequence		Length	Mass (Da)
	P05231-1 [UniParc]. Last modified August 13, 1987. Version 1. Checksum: 1F1ED1FE1B734079	FASTA	212	23,718
	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

References

	« Hide 'large scale' referencesShow '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.

Web resources

R&D Systems' cytokine mini-reviews: IL-6

Wikipedia

Interleukin-6 entry

SeattleSNPs

SHMPD

The Singapore human mutation and polymorphism database

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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.

IPI

IPI00007793.

PIR

IVHUB2. A32648.

RefSeq

NP_000591.1.

UniGene

Hs.654458

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1ALU	X-ray	1.90	A	28-212	[»]
1IL6	NMR	-	A	28-212	[»]
1N2Q	model	-	E/F	30-212	[»]
1P9M	X-ray	3.65	B	29-212	[»]
2IL6	NMR	-	A	28-212	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-482N.

IntAct

P05231. 4 interactions.

STRING

P05231.

Proteomic databases

PRIDE

P05231.

Genome annotation databases

Ensembl

ENST00000258743; ENSP00000258743; ENSG00000136244; Homo sapiens. [Genome view]
ENST00000404625; ENSP00000385675; ENSG00000136244; Homo sapiens. [Genome view]

GeneID

3569.

KEGG

hsa:3569.

UCSC

uc003svj.2. human.

Organism-specific databases

CTD

3569.

GeneCards

GC07P022732.

H-InvDB

HIX0006514.

HGNC

HGNC:6018. IL6.

HPA

CAB023406.

MIM

147620. gene.
148000. phenotype.
604302. phenotype.

Orphanet

92. Juvenile Idiopathic Arthritis.

PharmGKB

PA198.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG13272.

HOVERGEN

P05231.

InParanoid

P05231.

OMA

LQFSLRA.

OrthoDB

EOG9H48PT.

PhylomeDB

P05231.

Enzyme and pathway databases

Pathway_Interaction_DB

amb2_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

ArrayExpress

P05231.

Bgee

P05231.

CleanEx

HS_IL6.

Genevestigator

P05231.

GermOnline

ENSG00000136244. Homo sapiens.

Family and domain databases

InterPro

IPR009079. 4_helix_cytokine-like_core.
IPR003573. IL6_MGF_GCSF.
IPR003574. Interleukin_6.
[Graphical view]

PANTHER

PTHR11457. Interleukin_6. 1 hit.

Pfam

PF00489. IL6. 1 hit.
[Graphical view]

PIRSF

PIRSF001935. IL6_MGF_GCSF. 1 hit.

PRINTS

PR00433. IL6GCSFMGF.
PR00434. INTERLEUKIN6.

SMART

SM00126. IL6. 1 hit.
[Graphical view]

PROSITE

PS00254. INTERLEUKIN_6. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

DrugBank

DB01169. Arsenic trioxide.
DB01128. Bicalutamide.
DB01404. Ginseng.
DB00641. Simvastatin.

NextBio

13950.

PMAP-CutDB

P05231.

SOURCE

Search...

Entry information

Entry name

IL6_HUMAN

Accession

Primary (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 status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any 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.