Interleukin 6

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Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. Interleukin 6_sentence_0

In humans, it is encoded by the IL6 gene. Interleukin 6_sentence_1

In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Interleukin 6_sentence_2

Smooth muscle cells in the tunica media of many blood vessels also produce IL-6 as a pro-inflammatory cytokine. Interleukin 6_sentence_3

IL-6's role as an anti-inflammatory myokine is mediated through its inhibitory effects on TNF-alpha and IL-1, and activation of IL-1ra and IL-10. Interleukin 6_sentence_4

There is some early evidence that IL-6 can be used as an inflammatory marker for severe COVID-19 infection with poor prognosis, in the context of the wider coronavirus pandemic. Interleukin 6_sentence_5

Function Interleukin 6_section_0

Immune system Interleukin 6_section_1

IL-6 is secreted by macrophages in response to specific microbial molecules, referred to as pathogen-associated molecular patterns (PAMPs). Interleukin 6_sentence_6

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). Interleukin 6_sentence_7

These are present on the cell surface and intracellular compartments and induce intracellular signaling cascades that give rise to inflammatory cytokine production. Interleukin 6_sentence_8

IL-6 is an important mediator of fever and of the acute phase response. Interleukin 6_sentence_9

IL-6 is responsible for stimulating acute phase protein synthesis, as well as the production of neutrophils in the bone marrow. Interleukin 6_sentence_10

It supports the growth of B cells and is antagonistic to regulatory T cells. Interleukin 6_sentence_11

Metabolic Interleukin 6_section_2

It is capable of crossing the blood-brain barrier and initiating synthesis of PGE2 in the hypothalamus, thereby changing the body's temperature setpoint. Interleukin 6_sentence_12

In muscle and fatty tissue, IL-6 stimulates energy mobilization that leads to increased body temperature. Interleukin 6_sentence_13

At 4 degrees 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. Interleukin 6_sentence_14

In the absence of inflmammation 10-35% of circulating IL-6 may come from adipose tissue. Interleukin 6_sentence_15

IL-6 is produced by adipocytes and is thought to be a reason why obese individuals have higher endogeneous levels of CRP. Interleukin 6_sentence_16

IL-6 may exert a tonic suppression of body fat in mature mice, given that IL-6 gene knockout causes mature onset obesity. Interleukin 6_sentence_17

Moreover, IL-6 can suppress body fat mass via effects at the level of the CNS. Interleukin 6_sentence_18

The antiobesity effect of IL-6 in rodents is exerted at the level of the brain, presumably the hypothalamus and the hindbrain.). Interleukin 6_sentence_19

On the other hand, enhanced central IL-6 trans-signaling may improve energy and glucose homeostasis in obesity Trans-signaling implicates that a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. Interleukin 6_sentence_20

The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6. Interleukin 6_sentence_21

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. Interleukin 6_sentence_22

Outside the CNS, it seems that IL-6 stimulates the production of GLP-1 in the endocrine pancreas and the gut. Interleukin 6_sentence_23

Amylin is another substance that can reduce body weight, and that may interact with IL-6. Interleukin 6_sentence_24

Amylin-induced IL-6 production in the ventromedial hypothalamus (VMH) is a possible mechanism by which amylin treatment could interacts with VMH leptin signaling to increase its effect on weight loss. Interleukin 6_sentence_25

Central nervous system Interleukin 6_section_3

Intranasally administered IL-6 has been shown to improve sleep-associated consolidation of emotional memories. Interleukin 6_sentence_26

There are indications of interactions between GLP-1 and IL-6 in several parts of the brain. Interleukin 6_sentence_27

One example is the parabrachial nuclei of the pons, where GLP-1 increases IL-6 levels and where IL-6 exerts a marked anti-obesity effect. Interleukin 6_sentence_28

Role as myokine Interleukin 6_section_4

IL-6 is also considered a myokine, a cytokine produced from muscle, which is elevated in response to muscle contraction. Interleukin 6_sentence_29

It is significantly elevated with exercise, and precedes the appearance of other cytokines in the circulation. Interleukin 6_sentence_30

During exercise, it is thought to act in a hormone-like manner to mobilize extracellular substrates and/or augment substrate delivery. Interleukin 6_sentence_31

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. Interleukin 6_sentence_32

Studies in mice with IL-6 gene knockout indicate that lack of IL-6 in mice affect exercise function. Interleukin 6_sentence_33

It has been shown that the reduction of abdominally obesity by exercise in human adults can be reversed by the IL-6 receptor blocking antibody tocilizumab. Interleukin 6_sentence_34

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. Interleukin 6_sentence_35

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. Interleukin 6_sentence_36

IL-6 has extensive anti-inflammatory functions in its role as a myokine. Interleukin 6_sentence_37

IL-6 was the first myokine that was found to be secreted into the blood stream in response to muscle contractions. Interleukin 6_sentence_38

Aerobic exercise provokes a systemic cytokine response, including, for example, IL-6, IL-1 receptor antagonist (IL-1ra), and IL-10. Interleukin 6_sentence_39

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. Interleukin 6_sentence_40

It has been consistently demonstrated that the plasma concentration of IL-6 increases during muscular exercise. Interleukin 6_sentence_41

This increase is followed by the appearance of IL-1ra and the anti-inflammatory cytokine IL-10. Interleukin 6_sentence_42

In general, the cytokine response to exercise and sepsis differs with regard to TNF-α. Interleukin 6_sentence_43

Thus, the cytokine response to exercise is not preceded by an increase in plasma-TNF-α. Interleukin 6_sentence_44

Following exercise, the basal plasma IL-6 concentration may increase up to 100-fold, but less dramatic increases are more frequent. Interleukin 6_sentence_45

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. Interleukin 6_sentence_46

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. Interleukin 6_sentence_47

IL-6 had previously been classified as a proinflammatory cytokine. Interleukin 6_sentence_48

Therefore, it was first thought that the exercise-induced IL-6 response was related to muscle damage. Interleukin 6_sentence_49

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. Interleukin 6_sentence_50

This finding clearly demonstrates that muscle damage is not required to provoke an increase in plasma IL-6 during exercise. Interleukin 6_sentence_51

As a matter of fact, eccentric exercise may result in a delayed peak and a much slower decrease of plasma IL-6 during recovery. Interleukin 6_sentence_52

Recent work has shown that both upstream and downstream signalling pathways for IL-6 differ markedly between myocytes and macrophages. Interleukin 6_sentence_53

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. Interleukin 6_sentence_54

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. Interleukin 6_sentence_55

IL-6, among an increasing number of other recently identified myokines, thus remains an important topic in myokine research. Interleukin 6_sentence_56

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. Interleukin 6_sentence_57

IL-6 was the first myokine that was found to be secreted into the blood stream in response to muscle contractions. Interleukin 6_sentence_58

Receptor Interleukin 6_section_5

Main article: Interleukin-6 receptor Interleukin 6_sentence_59

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). Interleukin 6_sentence_60

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. Interleukin 6_sentence_61

In contrast, the expression of CD126 is restricted to certain tissues. Interleukin 6_sentence_62

As IL-6 interacts with its receptor, it triggers the gp130 and IL-6R proteins to form a complex, thus activating the receptor. Interleukin 6_sentence_63

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). Interleukin 6_sentence_64

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. Interleukin 6_sentence_65

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). Interleukin 6_sentence_66

These cytokines are commonly referred to as the IL-6 like or gp130 utilising cytokines Interleukin 6_sentence_67

In addition to the membrane-bound receptor, a soluble form of IL-6R (sIL-6R) has been purified from human serum and urine. Interleukin 6_sentence_68

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. Interleukin 6_sentence_69

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. Interleukin 6_sentence_70

Interactions Interleukin 6_section_6

Interleukin-6 has been shown to interact with interleukin-6 receptor, glycoprotein 130, and Galectin-3. Interleukin 6_sentence_71

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. Interleukin 6_sentence_72

Role in disease Interleukin 6_section_7

IL-6 stimulates the inflammatory and auto-immune processes in many diseases such as Multiple sclerosis, Neuromyelitis Optica Spectrum Disorder (NMOSD), diabetes, atherosclerosis, depression, Alzheimer's Disease, systemic lupus erythematosus, multiple myeloma, prostate cancer, Behçet's disease, rheumatoid arthritis, and intracerebral hemorrhage. Interleukin 6_sentence_73

Hence, there is an interest in developing anti-IL-6 agents as therapy against many of these diseases. Interleukin 6_sentence_74

The first such is tocilizumab, which has been approved for rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis. Interleukin 6_sentence_75

Others are in clinical trials. Interleukin 6_sentence_76

Rheumatoid arthritis Interleukin 6_section_8

The first FDA approved anti-IL-6 treatment was for rheumatoid arthritis. Interleukin 6_sentence_77

Cancer Interleukin 6_section_9

Anti-IL-6 therapy was initially developed for treatment of autoimmune diseases, but due to the role of IL-6 in chronic inflammation, IL-6 blockade was also evaluated for cancer treatment. Interleukin 6_sentence_78

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. Interleukin 6_sentence_79

Advanced/metastatic cancer patients have higher levels of IL-6 in their blood. Interleukin 6_sentence_80

One example of this is pancreatic cancer, with noted elevation of IL-6 present in patients correlating with poor survival rates. Interleukin 6_sentence_81

Diseases Interleukin 6_section_10

Enterovirus 71 Interleukin 6_section_11

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. Interleukin 6_sentence_82

EV71 patients with a certain gene polymorphism in IL-6 also appear to be more susceptible to developing encephalitis. Interleukin 6_sentence_83

Epigenetic modifications Interleukin 6_section_12

IL-6 has been shown to lead to several neurological diseases through its impact on epigenetic modification within the brain. Interleukin 6_sentence_84

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). Interleukin 6_sentence_85

IL-6 activated PKB can phosphorylate the nuclear localization signal on DNA methyltransferase-1 (DNMT1). Interleukin 6_sentence_86

This phosphorylation causes movement of DNMT1 to the nucleus, where it can be transcribed. Interleukin 6_sentence_87

DNMT1 recruits other DNMTs, including DNMT3A and DNMT3B, which, as a complex, recruit HDAC1. Interleukin 6_sentence_88

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. Interleukin 6_sentence_89

Increased IL-6, therefore, can hypermethylate DNA sequences and subsequently decrease gene expression through its effects on DNMT1 expression. Interleukin 6_sentence_90

Schizophrenia Interleukin 6_section_13

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. Interleukin 6_sentence_91

This hypermethylation may potentially lead to the decreased GAD67 levels seen in the brains of people with schizophrenia. Interleukin 6_sentence_92

GAD67 may be involved in the pathology of schizophrenia through its effect on GABA levels and on neural oscillations. Interleukin 6_sentence_93

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. Interleukin 6_sentence_94

These neural oscillations are impaired in schizophrenia, and these alterations may be responsible for both positive and negative symptoms of schizophrenia. Interleukin 6_sentence_95

Depression and major depressive disorder Interleukin 6_section_14

See also: Epigenetics of depression § Brain-derived neurotrophic factor, Epigenetics of schizophrenia#Methylation of BDNF Interleukin 6_sentence_96

The epigenetic effects IL-6 have also been implicated in the pathology of depression. Interleukin 6_sentence_97

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. Interleukin 6_sentence_98

Altered BDNF function has been implicated in depression, which is likely due to epigenetic modification following IL-6 upregulation. Interleukin 6_sentence_99

BDNF is a neurotrophic factor implicated in spine formation, density, and morphology on neurons. Interleukin 6_sentence_100

Downregulation of BDNF, therefore, may cause decreased connectivity in the brain. Interleukin 6_sentence_101

Depression is marked by altered connectivity, in particular between the anterior cingulate cortex and several other limbic areas, such as the hippocampus. Interleukin 6_sentence_102

The anterior cingulate cortex is responsible for detecting incongruences between expectation and perceived experience. Interleukin 6_sentence_103

Altered connectivity of the anterior cingulate cortex in depression, therefore, may cause altered emotions following certain experiences, leading to depressive reactions. Interleukin 6_sentence_104

This altered connectivity is mediated by IL-6 and its effect on epigenetic regulation of BDNF. Interleukin 6_sentence_105

Additional preclinical and clinical data, suggest that Substance P [SP] and IL-6 may act in concert to promote major depression. Interleukin 6_sentence_106

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. Interleukin 6_sentence_107

However, both IL6 and SP mitigate expression of BDNF in brain regions associated with negative affect and memory. Interleukin 6_sentence_108

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. Interleukin 6_sentence_109

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. Interleukin 6_sentence_110

Data suggest that nuclear translocation of NF-κB regulates IL-6 overexpression in SP-stimulated cells. Interleukin 6_sentence_111

This is of key interest as: 1) a meta-analysis indicates an association of major depressive disorder, C-reactive protein and IL6 plasma concentrations, 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. Interleukin 6_sentence_112

(see Summary of NK1RAs in Major Depression), 3) the preliminary observation that plasma concentrations of IL6 are elevated in depressed patients with cancer, and 4) selective NK1RAs may eliminate endogenous SP stress-induced augmentation of IL-6 secretion pre-clinically. Interleukin 6_sentence_113

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. Interleukin 6_sentence_114

The IL-6 antibody sirukumab is now undergoing clinical trials against major depressive disorder. Interleukin 6_sentence_115

Asthma Interleukin 6_section_15

Obesity is a known risk factor in the development of severe asthma. Interleukin 6_sentence_116

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. Interleukin 6_sentence_117

Protein superfamily Interleukin 6_section_16

Interleukin is the main member of the IL-6 superfamily (Pfam ), which also includes G-CSF, IL23A, and CLCF1. Interleukin 6_sentence_118

A viral version of IL6 is found in Kaposi's sarcoma-associated herpesvirus. Interleukin 6_sentence_119

Credits to the contents of this page go to the authors of the corresponding Wikipedia page: 6.