IL6 (interleukin 6 (interferon beta 2))

2007-03-01   Stefan Nagel , Roderick A F MacLeod 

DSMZ - German Collection of Microorganisms, Cell Cultures, Dept of Human & Animal Cell Cultures, Inhoffenstr. 7b, 38124, Braunschweig, Germany




Atlas Image
The gene for IL6 is shown in light blue and comprizes 6 exons (with 375 bp, 103 bp, 191 bp, 114 bp, 147 bp and 542 bp in length) and 5 introns (with 920 bp, 162 bp, 1058 bp, 707 bp and 1745 bp in length). The coding part is shown in dark blue.


6 exons.


1472 bp transcript with a 639 bp of coding sequence.


Atlas Image
The IL6 protein (shown in light green) shares C-terminal a homologous region (shown in dark green) also found in IL23A and CSF3.


212 amino acids, 23.7 kd, containing 4 alpha-helices.


IL6 shares sequence homology with IL23 (IL23A) and G-CSF (CSF3).



G/C polymorphism at nucleotide -174 (promoter region)
Breast cancer prognosis differs between populations. Despite its lower incidence in Blacks when compared to Caucasians, mortality among the former is higher. Genetic factors involved in the molecular pathways regulating tumor development have been adduced to explain these differences, and it has been suggested that the IL-6 gene is a susceptibility factor underlying ethnic differences in breast cancer survival. Reports of a G/C polymorphism at nucleotide -174 within the promoter region of the IL-6 gene support this contention. This polymorphism modulates IL-6 expression and allele/genotype frequencies at the -174 site differ significantly between ethnic groups.

Implicated in

Entity name
Various cancers
Although IL6 necessary to support growth of multiple myeloma cells, and is upregulated in certain tumor types, notably lung (squamous), bladder and prostate carcinomas, no recurrent chromosome rearrangements at 7p21 or IL6 rearrangements have been observed in these neoplasms.
Entity name
Breast cancer
No rearrangements reported.
Some cytokines, including IL-6, stimulate breast cancer proliferation or invasion and serve as negative prognostic indicators. Hitherto IL-2, IFNalpha, IFNbeta IFNgamma, IL-6, IL-12 have been used for anti tumour treatment of advanced breast cancer either to induce or increase hormone sensitivity and/or to stimulate cellular immunity. Cytokines, such as IL-6 play a key role in regulating estrogen synthesis in normal and malignant breast tissues. The activities of estradiol 17beta-hydroxysteroid dehydrogenase and estrone sulfatase are all increased by IL-6. Prostaglandin E2 may also be an important regulator of estradiol activity in breast tumors while invading macrophages and lymphocytes may also stimulate estrogen synthesis in breast cancers.
Entity name
No rearrangements reported.
Although interleukin-6 (IL-6) is considered as a key growth factor for myeloma cells, only a few subpopulations of tumor cells, such as CD45(+) immature cells, proliferate in response to IL-6. However, increasing numbers of cytokines, chemokines and cell-to-cell contacts been support growth of MM cells. It has repeatedly shown that oncogenic mutations as well as the bone marrow matrix (BMM) stimulate IL-6-independent signalling pathways that protect MM cells from apoptosis.Hyperdiploid MM tumors contain multiple trisomies involving chromosomes 3, 5, 7, 9, 11, 15 , 19 , and 21, but rarely have IgH translocations, although CCND-1/CCND-2/CCND-3 dysregulation appears to occur as an early event. This may sensitize these cells to proliferative stimuli, resulting in selective expansion as a result of interaction with BMM that produce IL-6 and other cytokines.
Three types of growth factors have been identified in plasma cells:
- The IL-6 family cytokines, which activate the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein (MAP) kinase pathways;
- Growth factors activating the phosphatidylinositol (PI)-3 kinase/AKT and MAP kinase pathways, and
- B-cell-activating factor (BAFF) or proliferation-inducing ligand (APRIL).
These growth factors may operate synergetically being co-localized together with cytoplasmic transduction elements in membrane caveolae.
Proteasome inhibitors are emerging as a promising class of anti-cancer therapeutic agents in MM, e.g. bortezomib which inhibits NF-kappaB translocation / transcription and critical signalling pathways, notably IL-6-induced proliferation and/or survival.
Entity name
Prostate cancer
No rearrangements reported.
IL-6 induces divergent proliferative responses in prostate cells. IL-6 is expressed in benign and malignant prostate tissue and levels of both IL-6 and IL-6R increase during prostate carcinogenesis. Serum levels of IL-6 are elevated in patients with treatment-refractory prostate carcinoma.IL-6 has also been shown to promote prostate cell growth, except in LNCaP cells, in which arrest and differentiation are produced. IL-6 induces activation of the androgen receptor (AR) in the absence of androgen. IL-6 also modulates vascular endothelial growth factor expression and neuroendocrine differentiation in prostate cells. Anti-IL-6 antibodies showed an inhibitory effect on PC-3 xenografts. Hence, IL-6 is widely considered a promising potential therapeutic target in prostate cancer.
Androgen receptor (AR), which is generally expressed in prostate cancers, promotes tumor progression in various ways, including ligand-independent activation. IL-6 is among the most important nonsteroidal regulators of AR activity reaching about half the maximum levels achieved by AR alone. At low concentrations of androgen, IL-6 and androgen operate synergistically to activate AR.
In prostate carcinoma cells homeodomain protein GBX2 was identified to contribute directly to IL6 expression by binding within the promoter region containing the consensus sequence for GBX2.
Entity name
No rearrangements detected.
Hodgkin lymphoma (HL) cells express multiple cytokines, notably IL6, which contributes to the immunoreactive phenotype and of which high levels are associated with bad prognosis. Both transcription factors, NFkB and AP1 are constitutively activated in in HL cells driving expression of IL6 and also disturbing the pro/anti-apoptotic balance. Additionally, homeodomain protein HLXB9 contributes to the IL6 expression. HLXB9 is closely related to homeodomain protein GBX2 contributing to IL6 expression in prostate carcinoma cells. So, tumor type specific homeobox genes are involved in high level expression of IL6.
Entity name
Cancer cachexia
No rearrangements reported.
Unlike acute inflammation which is a defense response, chronic inflammation may promote cancer. Several pro-inflammatory gene products modulate apoptosis, proliferation, angiogenesis, invasion, and metastasis, including IL-6, which is subject to regulation by NF-kB, which is constitutively active in most tumors. About one-in-three cancer deaths are due to cachexia (wasting) following the hypercatabolism of the bodys carbon sources. Tumor-inflammatory responses encompass synthesis of cytokines, including IL-6 which induces cachexia by altering lipids and protein metabolism. IL-6-like cytokines inhibit lipid biosynthesis by adipocytes and cause the atrophy and increased catabolism of muscle protein. Reduced serum IL-6 levels induced by medroxyprogesterone acetate has been reported to exert an anti-cachectic effect in advanced breast cancer.


Pubmed IDLast YearTitleAuthors
95701351997IL-6-regulated transcription factors.Akira S et al
161299032005Involvement of IL-6 in the pathogenesis of inflammatory bowel disease and colon cancer.Atreya R et al
114178592001IL-6-like cytokines and cancer cachexia: consequences of chronic inflammation.Barton BE et al
21715451990Haemopoietic receptors and helical cytokines.Bazan JF et al
156091312004The interleukin-6 gene: a susceptibility factor that may contribute to racial and ethnic disparities in breast cancer mortality.Berger FG et al
167979702006Signalling and survival pathways in multiple myeloma.Bommert K et al
146072142003Role of the androgen receptor axis in prostate cancer.Culig Z et al
165987692006Androgen axis in prostate cancer.Culig Z et al
158388762005Interleukin-6 regulation of prostate cancer cell growth.Culig Z et al
125204812002Drug resistance and drug development in multiple myeloma.Dalton WS et al
106905292000Enhanced GBX2 expression stimulates growth of human prostate cancer cells via transcriptional up-regulation of the interleukin 6 gene.Gao AC et al
167613882005Bortezomib (Velcade)--a new therapeutic strategy for patients with refractory multiple myeloma.Goranov SE et al
127730952003Principles of interleukin (IL)-6-type cytokine signalling and its regulation.Heinrich PC et al
150904482004Advances in biology of multiple myeloma: clinical applications.Hideshima T et al
161991532005The role of IL-6 and STAT3 in inflammation and cancer.Hodge DR et al
171429552006Mitogenic signals initiated via interleukin-6 receptor complexes in cooperation with other transmembrane molecules in myelomas.Ishikawa H et al
157715642005Interleukin-6: from basic science to medicine--40 years in immunology.Kishimoto T et al
129538032003Survival and proliferation factors of normal and malignant plasma cells.Klein B et al
110297832000Regulation of interleukin-6 secretion from breast cancer cells and its clinical implications.Kurebayashi J et al
157727022005HLXB9 activates IL6 in Hodgkin lymphoma cell lines and is regulated by PI3K signalling involving E2F3.Nagel S et al
169311072006Cytokines in breast cancer.Nicolini A et al
146925152003Effects of all-trans retinoic acid (ATRA) on human myeloma cells.Otsuki T et al
118795662002The role of cytokines in regulating estrogen synthesis: implications for the etiology of breast cancer.Purohit A et al
167417362006Interleukin-6 and its receptor: from bench to bedside.Scheller J et al
91447661997Interleukin-6: structure-function relationships.Simpson RJ et al
156406232004Immunomodulation of multiple myeloma.Tohnya TM et al
145813342003Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence.Trikha M et al
34933221987Identification of the human 26-kD protein, interferon beta 2 (IFN-beta 2), as a B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor.Van Damme J et al

Other Information

Locus ID:

NCBI: 3569
MIM: 147620
HGNC: 6018
Ensembl: ENSG00000136244


dbSNP: 3569
ClinVar: 3569
TCGA: ENSG00000136244


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Toll-like receptor signaling pathwayKEGGko04620
Jak-STAT signaling pathwayKEGGko04630
Hematopoietic cell lineageKEGGko04640
Graft-versus-host diseaseKEGGko05332
Cytokine-cytokine receptor interactionKEGGhsa04060
Toll-like receptor signaling pathwayKEGGhsa04620
Jak-STAT signaling pathwayKEGGhsa04630
Hematopoietic cell lineageKEGGhsa04640
Pathways in cancerKEGGhsa05200
Graft-versus-host diseaseKEGGhsa05332
Prion diseasesKEGGko05020
Prion diseasesKEGGhsa05020
Hypertrophic cardiomyopathy (HCM)KEGGko05410
Hypertrophic cardiomyopathy (HCM)KEGGhsa05410
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Cytosolic DNA-sensing pathwayKEGGko04623
Cytosolic DNA-sensing pathwayKEGGhsa04623
Intestinal immune network for IgA productionKEGGko04672
Intestinal immune network for IgA productionKEGGhsa04672
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
African trypanosomiasisKEGGko05143
African trypanosomiasisKEGGhsa05143
Rheumatoid arthritisKEGGko05323
Rheumatoid arthritisKEGGhsa05323
Influenza AKEGGko05164
Influenza AKEGGhsa05164
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Salmonella infectionKEGGko05132
Salmonella infectionKEGGhsa05132
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
HIF-1 signaling pathwayKEGGhsa04066
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Inflammatory bowel disease (IBD)KEGGhsa05321
Inflammatory bowel disease (IBD)KEGGko05321
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
FoxO signaling pathwayKEGGhsa04068
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-6 signalingREACTOMER-HSA-1059683
Signal TransductionREACTOMER-HSA-162582
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
RAF-independent MAPK1/3 activationREACTOMER-HSA-112409
MAPK3 (ERK1) activationREACTOMER-HSA-110056
MAPK1 (ERK2) activationREACTOMER-HSA-112411
Cellular responses to stressREACTOMER-HSA-2262752
Cellular SenescenceREACTOMER-HSA-2559583
Senescence-Associated Secretory Phenotype (SASP)REACTOMER-HSA-2559582
Insulin resistanceKEGGhsa04931
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Interleukin-6 family signalingREACTOMER-HSA-6783589
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
Antifolate resistanceKEGGko01523
Antifolate resistanceKEGGhsa01523
Th17 cell differentiationKEGGko04659
Th17 cell differentiationKEGGhsa04659
Interleukin-4 and 13 signalingREACTOMER-HSA-6785807
Interleukin-10 signalingREACTOMER-HSA-6783783
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA142672077CRISPLD2GeneLiterature, MultilinkAnnotationassociated24926665
PA164713366Tumor necrosis factor alpha (TNF-alpha) inhibitorsChemicalClinicalAnnotationassociatedPD22158445, 24776844
PA164749390peginterferon alfa-2aChemicalVariantAnnotationassociatedPD
PA164784024peginterferon alfa-2bChemicalClinicalAnnotationassociatedPD
PA443434Arthritis, RheumatoidDiseaseClinicalAnnotationassociatedPD24253594
PA443635Cardiovascular DiseasesDiseaseClinicalAnnotationassociatedPD16607077
PA443750Colitis, UlcerativeDiseaseClinicalAnnotationassociatedPD24776844
PA446116Inflammatory Bowel DiseasesDiseaseClinicalAnnotationassociatedPD24776844
PA446863Hepatitis C, ChronicDiseaseClinicalAnnotation, VariantAnnotationassociatedPD


Pubmed IDYearTitleCitations
212961092011The pro- and anti-inflammatory properties of the cytokine interleukin-6.754
191885312009Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis.670
195974882009Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion.634
198789812009An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation.594
119845952002Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis.445
126065242003Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study.338
128401462003Chronic stress and age-related increases in the proinflammatory cytokine IL-6.315
214817882011Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer.313
180600362007IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland.290
195819282009Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells.261


Stefan Nagel ; Roderick A F MacLeod

IL6 (interleukin 6 (interferon beta 2))

Atlas Genet Cytogenet Oncol Haematol. 2007-03-01

Online version: