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IL6 (interleukin 6 (interferon beta 2))

Identity

Other namesinterleukin 6
interferon beta 2
IL-6
HSF
HGF
CDF
BSF2
IFNB2
HGNC (Hugo) IL6
LocusID (NCBI) 3569
Location 7p15.3
Location_base_pair Starts at 22766766 and ends at 22771621 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order cen. - - LOC221838 - IL6 - TOMM7 - DRCTNNB1A - tel. IMAGE

DNA/RNA

 
  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.
Description 6 exons.
Transcription 1472 bp transcript with a 639 bp of coding sequence.

Protein

 
  The IL6 protein (shown in light green) shares C-terminal a homologous region (shown in dark green) also found in IL23A and CSF3.
Description 212 amino acids, 23.7 kd, containing 4 alpha-helices.
Homology IL6 shares sequence homology with IL23 (IL23A) and G-CSF (CSF3).

Mutations

Note 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 Various cancers
Note 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 Breast cancer
Cytogenetics No rearrangements reported.
Oncogenesis 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 Multiple myeloma
Cytogenetics No rearrangements reported.
Oncogenesis 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 Prostate cancer
Cytogenetics No rearrangements reported.
Oncogenesis 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 Hodgkin lymphoma
Cytogenetics No rearrangements detected.
Oncogenesis 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 Cancer cachexia
Cytogenetics No rearrangements reported.
Oncogenesis 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 body's 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.
  

Other Leukemias implicated (Data extracted from papers in the Atlas)

Leukemias 11q23ChildAMLID1615

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065

External links

Nomenclature
HGNC (Hugo)IL6   6018
Cards
AtlasIL6ID519ch7p15
Entrez_Gene (NCBI)IL6  3569  interleukin 6
GeneCards (Weizmann)IL6
Ensembl (Hinxton)ENSG00000136244 [Gene_View]  chr7:22766766-22771621 [Contig_View]  IL6 [Vega]
ICGC DataPortalENSG00000136244
AceView (NCBI)IL6
Genatlas (Paris)IL6
WikiGenes3569
SOURCE (Princeton)NM_000600
Genomic and cartography
GoldenPath (UCSC)IL6  -  7p15.3   chr7:22766766-22771621 +  7p21-p15   [Description]    (hg19-Feb_2009)
EnsemblIL6 - 7p21-p15 [CytoView]
Mapping of homologs : NCBIIL6 [Mapview]
OMIM108010   125853   147620   148000   266600   604302   
Gene and transcription
Genbank (Entrez)A09363 AA721478 AK298013 AK298077 AK301141
RefSeq transcript (Entrez)NM_000600
RefSeq genomic (Entrez)AC_000139 NC_000007 NC_018918 NG_011640 NT_007819 NW_001839003 NW_004929329
Consensus coding sequences : CCDS (NCBI)IL6
Cluster EST : UnigeneHs.654458 [ NCBI ]
CGAP (NCI)Hs.654458
Alternative Splicing : Fast-db (Paris)GSHG0027198
Alternative Splicing GalleryENSG00000136244
Gene ExpressionIL6 [ NCBI-GEO ]     IL6 [ SEEK ]   IL6 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP05231 (Uniprot)
NextProtP05231  [Medical]
With graphics : InterProP05231
Splice isoforms : SwissVarP05231 (Swissvar)
Domaine pattern : Prosite (Expaxy)INTERLEUKIN_6 (PS00254)   
Domains : Interpro (EBI)4_helix_cytokine-like_core    4_helix_cytokine_core    IL-6    IL-6/IL-23/GCSF/MGF   
Related proteins : CluSTrP05231
Domain families : Pfam (Sanger)IL6 (PF00489)   
Domain families : Pfam (NCBI)pfam00489   
Domain families : Smart (EMBL)IL6 (SM00126)  
DMDM Disease mutations3569
Blocks (Seattle)P05231
PDB (SRS)1ALU    1IL6    1N2Q    1P9M    2IL6    4J4L    4NI7    4NI9   
PDB (PDBSum)1ALU    1IL6    1N2Q    1P9M    2IL6    4J4L    4NI7    4NI9   
PDB (IMB)1ALU    1IL6    1N2Q    1P9M    2IL6    4J4L    4NI7    4NI9   
PDB (RSDB)1ALU    1IL6    1N2Q    1P9M    2IL6    4J4L    4NI7    4NI9   
Human Protein AtlasENSG00000136244
Peptide AtlasP05231
HPRD00970
IPIIPI00167115   
Protein Interaction databases
DIP (DOE-UCLA)P05231
IntAct (EBI)P05231
FunCoupENSG00000136244
BioGRIDIL6
IntegromeDBIL6
STRING (EMBL)IL6
Ontologies - Pathways
QuickGOP05231
Ontology : AmiGOneutrophil apoptotic process  hepatic immune response  hepatic immune response  neutrophil mediated immunity  monocyte chemotaxis  positive regulation of acute inflammatory response  positive regulation of leukocyte chemotaxis  cytokine activity  cytokine activity  interleukin-6 receptor binding  interleukin-6 receptor binding  interleukin-6 receptor binding  protein binding  extracellular region  extracellular space  interleukin-6 receptor complex  negative regulation of protein kinase activity  acute-phase response  inflammatory response  humoral immune response  aging  growth factor activity  positive regulation of cell proliferation  positive regulation of cell proliferation  negative regulation of cell proliferation  regulation of cell shape  response to heat  response to cold  response to mechanical stimulus  external side of plasma membrane  regulation of vascular endothelial growth factor production  negative regulation of lipid storage  cell growth  cytokine-mediated signaling pathway  platelet activation  response to caffeine  endocrine pancreas development  neuron projection development  response to nutrient levels  response to peptidoglycan  positive regulation of chemokine production  positive regulation of chemokine production  positive regulation of interleukin-6 production  response to insulin  negative regulation of collagen biosynthetic process  positive regulation of peptidyl-serine phosphorylation  positive regulation of protein import into nucleus, translocation  positive regulation of T cell proliferation  response to drug  positive regulation of tyrosine phosphorylation of Stat3 protein  defense response to protozoan  positive regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  response to amino acid  positive regulation of MAPK cascade  negative regulation of chemokine biosynthetic process  regulation of circadian sleep/wake cycle, non-REM sleep  positive regulation of nitric oxide biosynthetic process  cell redox homeostasis  negative regulation of fat cell differentiation  positive regulation of T-helper 2 cell differentiation  positive regulation of neuron differentiation  positive regulation of osteoblast differentiation  negative regulation of gluconeogenesis  positive regulation of translation  positive regulation of DNA replication  regulation of angiogenesis  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of JAK-STAT cascade  response to antibiotic  muscle cell cellular homeostasis  bone remodeling  negative regulation of hormone secretion  negative regulation of muscle organ development  positive regulation of smooth muscle cell proliferation  positive regulation of epithelial cell proliferation  negative regulation of cytokine secretion  positive regulation of peptidyl-tyrosine phosphorylation  defense response to Gram-negative bacterium  defense response to Gram-positive bacterium  positive regulation of B cell activation  positive regulation of immunoglobulin secretion  positive regulation of sequence-specific DNA binding transcription factor activity  positive regulation of NF-kappaB transcription factor activity  response to glucocorticoid  response to calcium ion  response to electrical stimulus  defense response to virus  positive regulation of protein kinase B signaling  positive regulation of transmission of nerve impulse  branching involved in salivary gland morphogenesis  epithelial cell proliferation involved in salivary gland morphogenesis  glucagon secretion  interleukin-6-mediated signaling pathway  cellular response to hydrogen peroxide  positive regulation of ERK1 and ERK2 cascade  cellular response to lipopolysaccharide  T-helper 17 cell lineage commitment  negative regulation of neuron death  positive regulation of STAT protein import into nucleus  positive regulation of type B pancreatic cell apoptotic process  
Ontology : EGO-EBIneutrophil apoptotic process  hepatic immune response  hepatic immune response  neutrophil mediated immunity  monocyte chemotaxis  positive regulation of acute inflammatory response  positive regulation of leukocyte chemotaxis  cytokine activity  cytokine activity  interleukin-6 receptor binding  interleukin-6 receptor binding  interleukin-6 receptor binding  protein binding  extracellular region  extracellular space  interleukin-6 receptor complex  negative regulation of protein kinase activity  acute-phase response  inflammatory response  humoral immune response  aging  growth factor activity  positive regulation of cell proliferation  positive regulation of cell proliferation  negative regulation of cell proliferation  regulation of cell shape  response to heat  response to cold  response to mechanical stimulus  external side of plasma membrane  regulation of vascular endothelial growth factor production  negative regulation of lipid storage  cell growth  cytokine-mediated signaling pathway  platelet activation  response to caffeine  endocrine pancreas development  neuron projection development  response to nutrient levels  response to peptidoglycan  positive regulation of chemokine production  positive regulation of chemokine production  positive regulation of interleukin-6 production  response to insulin  negative regulation of collagen biosynthetic process  positive regulation of peptidyl-serine phosphorylation  positive regulation of protein import into nucleus, translocation  positive regulation of T cell proliferation  response to drug  positive regulation of tyrosine phosphorylation of Stat3 protein  defense response to protozoan  positive regulation of apoptotic process  negative regulation of apoptotic process  negative regulation of cysteine-type endopeptidase activity involved in apoptotic process  response to amino acid  positive regulation of MAPK cascade  negative regulation of chemokine biosynthetic process  regulation of circadian sleep/wake cycle, non-REM sleep  positive regulation of nitric oxide biosynthetic process  cell redox homeostasis  negative regulation of fat cell differentiation  positive regulation of T-helper 2 cell differentiation  positive regulation of neuron differentiation  positive regulation of osteoblast differentiation  negative regulation of gluconeogenesis  positive regulation of translation  positive regulation of DNA replication  regulation of angiogenesis  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  positive regulation of JAK-STAT cascade  response to antibiotic  muscle cell cellular homeostasis  bone remodeling  negative regulation of hormone secretion  negative regulation of muscle organ development  positive regulation of smooth muscle cell proliferation  positive regulation of epithelial cell proliferation  negative regulation of cytokine secretion  positive regulation of peptidyl-tyrosine phosphorylation  defense response to Gram-negative bacterium  defense response to Gram-positive bacterium  positive regulation of B cell activation  positive regulation of immunoglobulin secretion  positive regulation of sequence-specific DNA binding transcription factor activity  positive regulation of NF-kappaB transcription factor activity  response to glucocorticoid  response to calcium ion  response to electrical stimulus  defense response to virus  positive regulation of protein kinase B signaling  positive regulation of transmission of nerve impulse  branching involved in salivary gland morphogenesis  epithelial cell proliferation involved in salivary gland morphogenesis  glucagon secretion  interleukin-6-mediated signaling pathway  cellular response to hydrogen peroxide  positive regulation of ERK1 and ERK2 cascade  cellular response to lipopolysaccharide  T-helper 17 cell lineage commitment  negative regulation of neuron death  positive regulation of STAT protein import into nucleus  positive regulation of type B pancreatic cell apoptotic process  
Pathways : BIOCARTAErythrocyte Differentiation Pathway [Genes]    IL-10 Anti-inflammatory Signaling Pathway [Genes]    Cytokines and Inflammatory Response [Genes]    Cells and Molecules involved in local acute inflammatory response [Genes]    Cytokine Network [Genes]    Role of ERBB2 in Signal Transduction and Oncology [Genes]    IL 6 signaling pathway [Genes]    Low-density lipoprotein (LDL) pathway during atherogenesis [Genes]    Signal transduction through IL1R [Genes]    IL 5 Signaling Pathway [Genes]    IL 17 Signaling Pathway [Genes]    Regulation of hematopoiesis by cytokines [Genes]   
Pathways : KEGGCytokine-cytokine receptor interaction    HIF-1 signaling pathway    FoxO signaling pathway    PI3K-Akt signaling pathway    Toll-like receptor signaling pathway    NOD-like receptor signaling pathway    Cytosolic DNA-sensing pathway    Jak-STAT signaling pathway    Hematopoietic cell lineage    TNF signaling pathway    Intestinal immune network for IgA production    Non-alcoholic fatty liver disease (NAFLD)    Prion diseases    Salmonella infection    Pertussis    Legionellosis    Chagas disease (American trypanosomiasis)    African trypanosomiasis    Malaria    Amoebiasis    Tuberculosis    Hepatitis B    Measles    Influenza A    HTLV-I infection    Herpes simplex infection    Pathways in cancer    Transcriptional misregulation in cancer    Inflammatory bowel disease (IBD)    Rheumatoid arthritis    Graft-versus-host disease    Hypertrophic cardiomyopathy (HCM)   
REACTOMEP05231 [protein]
REACTOME PathwaysREACT_120956 Cellular responses to stress [pathway]
REACTOME PathwaysREACT_6900 Immune System [pathway]
Protein Interaction DatabaseIL6
Wikipedia pathwaysIL6
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)IL6
SNP (GeneSNP Utah)IL6
SNP : HGBaseIL6
Genetic variants : HAPMAPIL6
1000_GenomesIL6 
ICGC programENSG00000136244 
CONAN: Copy Number AnalysisIL6 
Somatic Mutations in Cancer : COSMICIL6 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)TBsLVD Tuberculosis susceptibility Locus Variation Database
DECIPHER (Syndromes)7:22766766-22771621
Mutations and Diseases : HGMDIL6
OMIM108010    125853    147620    148000    266600    604302   
MedgenIL6
GENETestsIL6
Disease Genetic AssociationIL6
Huge Navigator IL6 [HugePedia]  IL6 [HugeCancerGEM]
Genomic VariantsIL6  IL6 [DGVbeta]
Exome VariantIL6
dbVarIL6
ClinVarIL6
snp3D : Map Gene to Disease3569
DGIdb (Curated mutations)IL6
DGIdb (Drug Gene Interaction db)IL6
General knowledge
Homologs : HomoloGeneIL6
Homology/Alignments : Family Browser (UCSC)IL6
Phylogenetic Trees/Animal Genes : TreeFamIL6
Chemical/Protein Interactions : CTD3569
Chemical/Pharm GKB GenePA198
Clinical trialIL6
Cancer Resource (Charite)ENSG00000136244
Other databases
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
CoreMineIL6
GoPubMedIL6
iHOPIL6

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Contributor(s)

Written03-2007Stefan Nagel, Roderick A F MacLeod

Citation

This paper should be referenced as such :
MacLeod, RAF ; Nagel, S
IL6 (interleukin 6 (interferon beta 2))
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3):226-228.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/IL6ID519ch7p15.html

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