Interleukin 6

Interleukin 6
PDB rendering based on 1ALU.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1ALU, 1IL6, 1N2Q, 1P9M, 2IL6, 4CNI, 4J4L, 4NI7, 4NI9, 4O9H
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 • interleukin-6 receptor binding • protein binding • growth factor activity Cellular component • extracellular region • extracellular space • cytoplasm • interleukin-6 receptor complex • external side of plasma membrane Biological process • neutrophil apoptotic process • response to yeast • 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 • negative regulation of cell proliferation • regulation of cell shape • response to heat • response to cold • regulation of vascular endothelial growth factor production • negative regulation of lipid storage • response to auditory stimulus • 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 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 • glucose homeostasis • 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 • cellular response to interleukin-1 • cellular response to interleukin-6 • cellular response to tumor necrosis factor • cellular response to dexamethasone stimulus • 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 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	NM_031168
RefSeq (protein)	NP_000591	NP_112445
Location (UCSC)	Chr 7: 22.73 – 22.73 Mb	Chr 5: 30.01 – 30.02 Mb
PubMed search	[1]	[2]

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene.

IL-6 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. IL-6 also plays a role in fighting infection, as IL-6 has been shown in mice to be required for resistance against bacterium Streptococcus pneumoniae.

In addition, 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 an important mediator of fever and of the acute phase response. It is capable of crossing the blood-brain barrier 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 that 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 an 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. Intranasally administered IL-6 has been shown to improve sleep-associated consolidation of emotional memories.

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.

Role as myokine

IL-6 is also considered a myokine, a cytokine produced from muscle, which is elevated in response to muscle contraction. 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.

IL-6 has extensive anti-inflammatory functions in its role as a myokine. IL-6 was the first myokine that was found to be secreted into the blood stream in response to muscle contractions. Aerobic exercise provokes a systemic cytokine response, including, for example, IL-6, IL-1 receptor antagonist (IL-1ra), and IL-10. IL-6 was serendipitously discovered as a myokine because of the observation that it increased in an exponential fashion proportional to the length of exercise and the amount of muscle mass engaged in the exercise. It has been consistently demonstrated that the plasma concentration of IL-6 increases during muscular exercise. This increase is followed by the appearance of IL-1ra and the anti-inflammatory cytokine IL-10. In general, the cytokine response to exercise and sepsis differs with regard to TNF-α. Thus, the cytokine response to exercise is not preceded by an increase in plasma-TNF-α. Following exercise, the basal plasma IL-6 concentration may increase up to 100-fold, but less dramatic increases are more frequent. The exercise-induced increase of plasma IL-6 occurs in an exponential manner and the peak IL-6 level is reached at the end of the exercise or shortly thereafter. It is the combination of mode, intensity, and duration of the exercise that determines the magnitude of the exercise-induced increase of plasma IL-6.

IL-6 had previously been classified as a proinflammatory cytokine. Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage. However, it has become evident that eccentric exercise is not associated with a larger increase in plasma IL-6 than exercise involving concentric "nondamaging" muscle contractions. This finding clearly demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. As a matter of fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery.

Recent work has shown that both upstream and downstream signalling pathways for IL-6 differ markedly between myocytes and macrophages. It appears that unlike IL-6 signalling in macrophages, which is dependent upon activation of the NFκB signalling pathway, intramuscular IL-6 expression is regulated by a network of signalling cascades, including the Ca2+/NFAT and glycogen/p38 MAPK pathways. Thus, when IL-6 is signalling in monocytes or macrophages, it creates a pro-inflammatory response, whereas IL-6 activation and signalling in muscle is totally independent of a preceding TNF-response or NFκB activation, and is anti-inflammatory.

IL-6, among an increasing number of other recently identified myokines, thus remains an important topic in myokine research. It appears in muscle tissue and in the circulation during exercise at levels up to one hundred times basal rates, as noted, and is seen as having a beneficial impact on health and bodily functioning when elevated in response to physical exercise. IL-6 was the first myokine that was found to be secreted into the blood stream in response to muscle contractions.

Receptor

Main article: Interleukin-6 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).

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). These cytokines are commonly referred to as the IL-6 like or gp130 utilising cytokines

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 and promote survival of neurons and, hence, may be important in nerve regeneration through remyelination.

Interactions

Interleukin 6 has been shown to interact with interleukin-6 receptor. and glycoprotein 130.

Role in disease

IL-6 stimulates the inflammatory and auto-immune processes in many diseases such as diabetes, atherosclerosis, depression, Alzheimer's Disease, systemic lupus erythematosus, multiple myeloma, prostate cancer, Behçet's disease, and rheumatoid arthritis.

Hence, there is an interest in developing anti-IL-6 agents as therapy against many of these diseases. The first such is tocilizumab, which has been approved for rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis. Others are in clinical trials.

Rheumatoid arthritis

The first FDA approved anti-IL-6 was for RA.

Cancer

Recently, Anestakis et al. outlined the interleukin mechanisms in cancer progression and possibilities in application for cancer immunotherapy in their systematic review. IL-6 was seen to have roles in tumor microenvironment regulation, production of breast cancer stem cell-like cells, metastasis through down-regulation of E-cadherin, and alteration of DNA methylation in oral cancer.

Advanced/metastatic cancer patients have higher levels of IL-6 in their blood. One example of this is pancreatic cancer, with noted elevation of IL-6 present in patients correlating with poor survival rates.

Infectious diseases

Enterovirus 71

High IL-6 levels are associated with the development of encephalitis in children and immunodeficient mouse models infected with Enterovirus 71; this highly contagious virus normally causes a milder illness called Hand, foot, and mouth disease but can cause life-threatening encephalitis in some cases. EV71 patients with a certain gene polymorphism in IL-6 also appear to be more susceptible to developing encephalitis.

Epigenetic modifications

IL-6 has been shown to lead to several neurological diseases through its impact on epigenetic modification within the brain. IL-6 activates the Phosphoinositide 3-kinase (PI3K) pathway, and a downstream target of this pathway is the protein kinase B (PKB) (Hodge et al., 2007). IL-6 activated PKB can phosphorylate the nuclear localization signal on DNA methyltransferase-1(DNMT1). This phosphorylation causes movement of DNMT1 to the nucleus, where it can be transcribed. DNMT1 recruits other DNMTs, including DNMT3A and DNMT3B, which, as a complex, recruit HDAC1. This complex adds methyl groups to CpG islands on gene promoters, repressing the chromatin structure surrounding the DNA sequence and inhibiting transcriptional machinery from accessing the gene to induce transcription. Increased IL-6, therefore, can hypermethylate DNA sequences and subsequently decrease gene expression through its effects on DNMT1 expression.

Schizophrenia

The induction of epigenetic modification by IL-6 has been proposed as a mechanism in the pathology of schizophrenia through the hypermethylation and repression of the GAD67 promoter. This hypermethylation may potentially lead to the decreased GAD67 levels seen in the brains of people with schizophrenia. GAD67 may be involved in the pathology of schizophrenia through its effect on GABA levels and on neural oscillations. Neural oscillations occur when inhibitory GABAergic neurons fire synchronously and cause inhibition of a multitude of target excitatory neurons at the same time, leading to a cycle of inhibition and disinhibition. These neural oscillations are impaired in schizophrenia, and these alterations may be responsible for both positive and negative symptoms of schizophrenia.

Depression

The epigenetic effects IL-6 have also been implicated in the pathology of depression. The effects of IL-6 on depression are mediated through the repression of brain-derived neurotrophic factor (BDNF) expression in the brain; DNMT1 hypermethylates the BDNF promoter and reduces BDNF levels. Altered BDNF function has been implicated in depression, which is likely due to epigenetic modification following IL-6 upregulation. BDNF is a neutrophic factor implicated in spine formation, density, and morphology on neurons. Downregulation of BDNF, therefore, may cause decreased connectivity in the brain. Depression is marked by altered connectivity, in particular between the anterior cingulate cortex and several other limbic areas, such as the hippocampus. The anterior cingulate cortex is responsible for detecting incongruences between expectation and perceived experience. Altered connectivity of the anterior cingulate cortex in depression, therefore, may cause altered emotions following certain experiences, leading to depressive reactions. This altered connectivity is mediated by IL-6 and its effect on epigenetic regulation of BDNF.

External links

• IL-6 expression in various cancers