Interleukin 6 (interferon, beta 2)
PDB rendering based on 1ALU.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1ALU, 1IL6, 1P9M, 2IL6
Identifiers
Symbols	IL6; BSF2; HGF; HSF; IFNB2; IL-6
External IDs	OMIM: 147620 MGI: 96559 HomoloGene: 502 ChEMBL: 1795129 GeneCards: IL6 Gene
Gene Ontology Molecular function • cytokine activity • cytokine activity • interleukin-6 receptor binding • interleukin-6 receptor binding • interleukin-6 receptor binding • growth factor activity Cellular component • extracellular region • extracellular space • interleukin-6 receptor complex • external side of plasma membrane Biological process • neutrophil apoptosis • hepatic immune response • hepatic immune response • neutrophil mediated immunity • monocyte chemotaxis • positive regulation of acute inflammatory response • positive regulation of leukocyte chemotaxis • negative regulation of protein kinase activity • acute-phase response • inflammatory response • humoral immune response • aging • 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 • response to bacterium • regulation of vascular endothelial growth factor production • negative regulation of lipid storage • response to organic cyclic compound • cell growth • cytokine-mediated signaling pathway • platelet activation • response to caffeine • endocrine pancreas development • neuron projection development • response to nutrient levels • response to peptidoglycan • response to lipopolysaccharide • positive regulation of chemokine production • positive regulation of chemokine production • positive regulation of interleukin-6 production • response to insulin stimulus • negative regulation of collagen biosynthetic process • positive regulation of peptidyl-serine phosphorylation • positive regulation of protein import into nucleus, translocation • response to cytokine stimulus • positive regulation of T cell proliferation • T cell activation • response to drug • positive regulation of tyrosine phosphorylation of Stat3 protein • defense response to protozoan • regulation of apoptotic process • negative regulation of apoptotic process • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process • response to amino acid stimulus • positive regulation of MAPK cascade • neuroprotection • 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 anti-apoptosis • positive regulation of transcription, DNA-dependent • positive regulation of transcription from RNA polymerase II promoter • positive regulation of JAK-STAT cascade • response to antibiotic • muscle cell 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 stimulus • response to calcium ion • response to electrical stimulus • defense response to virus • positive regulation of protein kinase B signaling cascade • 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 • positive regulation of STAT protein import into nucleus Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3569	16193
Ensembl	ENSG00000136244	ENSMUSG00000025746
UniProt	P05231	P08505
RefSeq (mRNA)	NM_000600.3	NM_031168.1
RefSeq (protein)	NP_000591.1	NP_112445.1
Location (UCSC)	Chr 7: 22.77 – 22.77 Mb	Chr 5: 30.34 – 30.35 Mb
PubMed search	[1]	[2]
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Interleukin-6 (IL-6) is a protein that in humans is encoded by the IL6 gene.^[1]

IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other tissue damage leading to inflammation. In terms of host response to a foreign pathogen during infection, IL-6 has been shown, in mice, to be required for resistance against the bacterium Streptococcus pneumoniae.^[2] IL-6 is also a "myokine," a cytokine produced from muscle, and is elevated in response to muscle contraction.^[3] It is significantly elevated with exercise, and precedes the appearance of other cytokines in the circulation. During exercise, it is thought to act in a hormone-like manner to mobilize extracellular substrates and/or augment substrate delivery.^[4] Additionally, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smooth muscle cells in the tunica media of many blood vessels also produce IL-6 as a pro-inflammatory cytokine. IL-6's role as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-alpha and IL-1, and activation of IL-1ra and IL-10.

  Function

IL-6 is one of the most important mediators of fever and of the acute phase response. It is capable of crossing the blood brain barrier^[5] and initiating synthesis of PGE2 in the hypothalamus, thereby changing the body's temperature setpoint. In muscle and fatty tissue, IL-6 stimulates energy mobilization which leads to increased body temperature. IL-6 can be secreted by macrophages in response to specific microbial molecules, referred to as pathogen associated molecular patterns (PAMPs). These PAMPs bind to highly important group of detection molecules of the innate immune system, called pattern recognition receptors (PRRs), including Toll-like receptors (TLRs). These are present on the cell surface and intracellular compartments and induce intracellular signaling cascades that give rise to inflammatory cytokine production.

IL-6 is also essential for hybridoma growth and is found in many supplemental cloning media such as briclone. Inhibitors of IL-6 (including estrogen) are used to treat postmenopausal osteoporosis. IL-6 is also produced by adipocytes and is thought to be a reason why obese individuals have higher endogeneous levels of CRP^[6]. In a 2009 study, intranasally administered IL-6 was shown to improve sleep-associated consolidation of emotional memories.^[7]

IL-6 is responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. It supports the growth of B cells and is antagonistic to regulatory T cells.

  Receptor

IL-6 signals through a cell-surface type I cytokine receptor complex consisting of the ligand-binding IL-6Rα chain (CD126), and the signal-transducing component gp130 (also called CD130). CD130 is the common signal transducer for several cytokines including leukemia inhibitory factor(LIF), ciliary neurotropic factor, oncostatin M, IL-11 and cardiotrophin-1, and is almost ubiquitously expressed in most tissues. In contrast, the expression of CD126 is restricted to certain tissues. As IL-6 interacts with its receptor, it triggers the gp130 and IL-6R proteins to form a complex, thus activating the receptor. These complexes bring together the intracellular regions of gp130 to initiate a signal transduction cascade through certain transcription factors, Janus kinases (JAKs) and Signal Transducers and Activators of Transcription (STATs).^[8]

IL-6 is probably the best studied of the cytokines that use gp130, also known as IL-6 signal transducer (IL6ST), in their signalling complexes. Other cytokines that signal through receptors containing gp130 are Interleukin 11 (IL-11), Interleukin 27 (IL-27), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), leukemia inhibitory factor (LIF), oncostatin M (OSM), Kaposi's sarcoma-associated herpesvirus interleukin 6 like protein (KSHV-IL6).^[9] These cytokines are commonly referred to as the IL-6 like or gp130 utilising cytokines ^[10]

In addition to the membrane-bound receptor, a soluble form of IL-6R (sIL-6R) has been purified from human serum and urine. Many neuronal cells are unresponsive to stimulation by IL-6 alone, but differentiation and survival of neuronal cells can be mediated through the action of sIL-6R. The sIL-6R/IL-6 complex can stimulate neurites outgrowth promote survival of neurons, hence may be important in nerve regeneration through remyelination.

  Interactions

Interleukin 6 has been shown to interact with interleukin-6 receptor.^[11][12][13] and glycoprotein 130.^[14]

  Role in disease

IL-6 is relevant to many diseases such as diabetes,^[15] atherosclerosis,^[16] depression,^[17] Alzheimer's Disease,^[18] systemic lupus erythematosus,^[19] prostate cancer,^[20] and rheumatoid arthritis.^[21]

Advanced/metastatic cancer patients have higher levels of IL-6 in their blood.^[22] Hence there is an interest in developing anti-IL-6 agents as therapy against many of these diseases.^[23][24] The first such is tocilizumab which has been approved for rheumatoid arthritis. Another, ALD518, is in clinical trials.

  References

  Further reading

  External links

• IL-6 expression in various cancers
• Companion Reviews and Search Terms on Interleukin 6

PDB gallery 1alu: HUMAN INTERLEUKIN-6   1il6: HUMAN INTERLEUKIN-6, NMR, MINIMIZED AVERAGE STRUCTURE   1p9m: Crystal structure of the hexameric human IL-6/IL-6 alpha receptor/gp130 complex   2il6: HUMAN INTERLEUKIN-6, NMR, 32 STRUCTURES