Interleukin 6

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

IL-6 is secreted by is_associated_with::T cells and is_associated_with::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 is_associated_with::Streptococcus pneumoniae.

In addition, is_associated_with::osteoblasts secrete IL-6 to stimulate is_associated_with::osteoclast formation. is_associated_with::Smooth muscle cells in the is_associated_with::tunica media of many blood vessels also produce IL-6 as a pro-inflammatory is_associated_with::cytokine. IL-6's role as an anti-inflammatory cytokine is mediated through its inhibitory effects on is_associated_with::TNF-alpha and IL-1, and activation of IL-1ra and IL-10.

Function
IL-6 is an important mediator of is_associated_with::fever and of the is_associated_with::acute phase response. It is capable of crossing the is_associated_with::blood-brain barrier and initiating synthesis of PGE2 in the is_associated_with::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 is_associated_with::macrophages in response to specific microbial molecules, referred to as is_associated_with::pathogen-associated molecular patterns (PAMPs). These PAMPs bind to an important group of detection molecules of the is_associated_with::innate immune system, called is_associated_with::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 is_associated_with::hybridoma growth and is found in many supplemental cloning media such as is_associated_with::briclone. Inhibitors of IL-6 (including is_associated_with::estrogen) are used to treat postmenopausal is_associated_with::osteoporosis. IL-6 is also produced by is_associated_with::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 is_associated_with::neutrophils in the bone marrow. It supports the growth of is_associated_with::B cells and is antagonistic to regulatory T cells.

Role as myokine
IL-6 is also considered a is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::physical exercise. IL-6 was the first myokine that was found to be secreted into the blood stream in response to muscle contractions.

Receptor
IL-6 signals through a cell-surface is_associated_with::type I cytokine receptor complex consisting of the ligand-binding IL-6Rα chain (CD126), and the signal-transducing component is_associated_with::gp130 (also called CD130). CD130 is the common signal transducer for several cytokines including is_associated_with::leukemia inhibitory factor (LIF), is_associated_with::ciliary neurotropic factor, is_associated_with::oncostatin M, IL-11 and is_associated_with::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 is_associated_with::intracellular regions of gp130 to initiate a signal transduction cascade through certain is_associated_with::transcription factors, is_associated_with::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 is_associated_with::Interleukin 11 (IL-11), is_associated_with::Interleukin 27 (IL-27), is_associated_with::ciliary neurotrophic factor (CNTF), is_associated_with::cardiotrophin-1 (CT-1), cardiotrophin-like cytokine (CLC), is_associated_with::leukemia inhibitory factor (LIF), is_associated_with::oncostatin M (OSM), is_associated_with::Kaposi's sarcoma-associated herpesvirus interleukin 6-like protein (is_associated_with::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 is_associated_with::interleukin-6 receptor. and is_associated_with::glycoprotein 130.

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

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

Advanced/is_associated_with::metastatic cancer patients have higher levels of IL-6 in their blood. One example of this is is_associated_with::pancreatic cancer, with noted elevation of IL-6 present in patients correlating with poor survival rates. Hence, there is an interest in developing is_associated_with::anti-IL-6 agents as therapy against many of these diseases. The first such is is_associated_with::tocilizumab, which has been approved for is_associated_with::rheumatoid arthritis, is_associated_with::Castleman's disease and systemic juvenile idiopathic arthritis. Others are in clinical trials.

Enterovirus 71
High IL-6 levels are associated with the development of is_associated_with::encephalitis in children and immunodeficient mouse models infected with is_associated_with::Enterovirus 71; this highly contagious virus normally causes a milder illness called is_associated_with::Hand, foot, and mouth disease but can cause life-threatening encephalitis in some cases. EV71 patients with a certain is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::anterior cingulate cortex and several other limbic areas, such as the is_associated_with::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.