Interleukin 6
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Location (UCSC) | Chr 7: 22.73 – 22.73 Mb | Chr 5: 30.22 – 30.22 Mb | |||||||
PubMed search | [3] | [4] |
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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.[5]
In addition,
There is some early evidence that IL-6 can be used as an
Function
Immune system
IL-6 is secreted by
IL-6 is responsible for stimulating acute phase protein synthesis, as well as the production of
Metabolic
It is capable of crossing the blood–brain barrier[7] 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. At 4 °C, both the oxygen consumption and core temperature were lower in IL-6-/- compared with wild-type mice, suggesting a lower cold-induced thermogenesis in IL-6-/- mice.[8]
In the absence of inflammation 10–35% of circulating IL-6 may come from adipose tissue.
Studies in experimental animals indicate that IL-6 in the CNS partly mediates the suppression of food intake and body weight exerted by glucagon-like peptide-1 (GLP-1) receptor stimulation.[18]
Outside the CNS, it seems that IL-6 stimulates the production of GLP-1 in the endocrine pancreas and the gut.[19] Amylin is another substance that can reduce body weight, and that may interact with IL-6. Amylin-induced IL-6 production in the ventromedial hypothalamus (VMH) is a possible mechanism by which amylin treatment could interact with VMH leptin signaling to increase its effect on weight loss.[20]
It is assumed that interleukin 6 in the liver activates the homologue of the human longevity gene
Central nervous system
Intranasally administered IL-6 has been shown to improve sleep-associated consolidation of emotional memories.[23]
There are indications of interactions between GLP-1 and IL-6 in several parts of the brain. One example is the parabrachial nuclei of the pons, where GLP-1 increases IL-6 levels[24][25] and where IL-6 exerts a marked anti-obesity effect.[26]
Role as myokine
IL-6 is also considered a myokine, a cytokine produced from muscle, which is elevated in response to muscle contraction.[27] 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.[28]
Like in humans, there seems to be an increase in IL-6 expression in working muscle and plasma IL-6 concentration during exercise in rodents.[29][30] Studies in mice with IL-6 gene knockout indicate that lack of IL-6 in mice affect exercise function.[9]
It has been shown that the reduction of abdominal obesity by exercise in human adults can be reversed by the IL-6 receptor blocking antibody tocilizumab. Together with the findings that IL-6 prevents obesity, stimulates lipolysis and is released from skeletal muscle during exercise, the tocilizumab finding indicates that IL-6 is required for exercise to reduce visceral adipose tissue mass.[31] Bone may be another organ affected by exercise induced IL-6, given that muscle-derived interleukin 6 has been reported to increase exercise capacity by signaling in osteoblasts.[32]
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.[33] 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.[34]
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.[35] 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.[34]
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.[36]
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
Receptor
IL-6 signals through a cell-surface
IL-6 is probably the best-studied of the cytokines that use
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
There is considerable functional overlap and interaction between Substance P (SP), the natural ligand for the neurokinin type 1 receptor (NK1R, a mediator of immunomodulatory activity) and IL-6.
Role in disease
IL-6 stimulates the inflammatory and auto-immune processes in many diseases such as
Hence, there is an interest in developing
Liver diseases
Since IL-6 is a well-known pleiotropic molecule, it plays a dual role in the pathogenesis of liver diseases. While it is necessary for promoting liver regeneration,[65] IL-6 is also a highly recognized marker of systemic inflammation and its association with mortality in liver diseases has been reported by multiple studies.[66][67][68][69][70] In patients with severe alcohol-associated hepatitis, IL-6 showed the most robust elevation among inflammatory cytokines compared to healthy controls with a further increase in non-survivors. In these patients, IL-6 was a predictor of short-term (28- and 90-day) mortality.[70]
Rheumatoid arthritis
The first FDA approved
Cancer
Advanced/
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
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
Aging
IL-6 is commonly found in the senescence-associated secretory phenotype (SASP) factors secreted by senescent cells (a toxic cell-type that increases with aging).[87][88] Cancer (a disease that increases with age) invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase, chemokine, IL-6, and interleukin 8 (IL-8).[89][87] IL-6 and IL-8 are the most conserved and robust features of SASP.[90]
Myelodysplastic Syndromes
IL-6 receptor was found upregulated in high-risk MDS patients. The inhibition of IL-6 signaling pathway can significantly ameliorate the clonogenicity of MDS hematopoietic stem and progenitor cells (HSPCs), but have undetectable effect on normal HSPCs.[73]
Depression and major depressive disorder
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.[91] Altered BDNF function has been implicated in depression,[92] which is likely due to epigenetic modification following IL-6 upregulation.[91] BDNF is a neurotrophic factor implicated in spine formation, density, and morphology on neurons.[93] 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.[94] The anterior cingulate cortex is responsible for detecting incongruences between expectation and perceived experience.[95] Altered connectivity of the anterior cingulate cortex in depression, therefore, may cause altered emotions following certain experiences, leading to depressive reactions.[95] This altered connectivity is mediated by IL-6 and its effect on epigenetic regulation of BDNF.[91]
Additional preclinical and clinical data, suggest that Substance P [SP] and IL-6 may act in concert to promote major depression. SP, a hybrid neurotransmitter-cytokine, is co-transmitted with BDNF through paleo-spinothalamic circuitry from the periphery with collaterals into key areas of the limbic system. However, both IL6 and SP mitigate expression of BDNF in brain regions associated with negative affect and memory. SP and IL6 both relax tight junctions of the blood brain barrier, such that effects seen in fMRI experiments with these molecules may be a bidirectional mix of neuronal, glial, capillary, synaptic, paracrine, or endocrine-like effects. At the cellular level, SP is noted to increase expression of interleukin-6 (IL-6) through PI-3K, p42/44 and p38 MAP kinase pathways. Data suggest that nuclear translocation of NF-κB regulates IL-6 overexpression in SP-stimulated cells.[96] This is of key interest as: 1) a meta-analysis indicates an association of major depressive disorder, C-reactive protein and IL6 plasma concentrations,[97] 2) NK1R antagonists [five molecules] studied by 3 independent groups in over 2000 patients from 1998 to 2013 validate the mechanism as dose-related, fully effective antidepressant, with a unique safety profile.[98][99] (see Summary of NK1RAs in Major Depression), 3) the preliminary observation that plasma concentrations of IL6 are elevated in depressed patients with cancer,[100] and 4) selective NK1RAs may eliminate endogenous SP stress-induced augmentation of IL-6 secretion pre-clinically.[101] These and many other reports suggest that a clinical study of a neutralizing IL-6 biological or drug based antagonist is likely warranted in patients with major depressive disorder, with or without co-morbid chronic inflammatory based illnesses; that the combination of NK1RAs and IL6 blockers may represent a new, potentially biomarkable approach to major depression, and possibly bipolar disorder.
The IL-6 antibody sirukumab is now undergoing clinical trials against major depressive disorder.[102]
Asthma
Obesity is a known risk factor in the development of severe asthma. Recent data suggests that the inflammation associated with obesity, potentially mediated by IL-6, plays a role in causing poor lung function and increased risk for developing asthma exacerbations.[103]
Protein superfamily
Interleukin is the main member of the IL-6 superfamily (
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