Interleukin 6

Last updated

IL6
IL6 Crystal Structure.rsh.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IL6 , BSF2, HGF, HSF, IFNB2, IL-6, BSF-2, CDF, IFN-beta-2, interleukin 6
External IDs OMIM: 147620; MGI: 96559; HomoloGene: 502; GeneCards: IL6; OMA:IL6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

3569

16193

Ensembl

ENSG00000136244

ENSMUSG00000025746

UniProt

P05231

P08505

RefSeq (mRNA)

NM_000600
NM_001318095
NM_001371096

NM_031168
NM_001314054

RefSeq (protein)

NP_000591
NP_001305024
NP_001358025

NP_001300983
NP_112445

Location (UCSC) Chr 7: 22.73 – 22.73 Mb Chr 5: 30.22 – 30.22 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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, 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 myokine is mediated through its inhibitory effects on TNF-alpha and IL-1 and its activation of IL-1ra and IL-10.

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. [6]

Function

Immune system

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

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.

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. [9] IL-6 is produced by adipocytes and is thought to be a reason why obese individuals have higher endogenous levels of CRP. [10] IL-6 may exert a tonic suppression of body fat in mature mice, given that IL-6 gene knockout causes mature onset obesity. [11] [12] [13] Moreover, IL-6 can suppress body fat mass via effects at the level of the CNS. [11] The antiobesity effect of IL-6 in rodents is exerted at the level of the brain, presumably the hypothalamus and the hindbrain. [14] [15] [16] On the other hand, enhanced central IL-6 trans-signaling may improve energy and glucose homeostasis in obesity [17] 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. 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. [17]

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 mINDY expression via binding to its IL-6-receptor, which is associated with activation of the transcription factor STAT3 (which binds to the binding site in the mIndy promoter) and thereby rise of citrate uptake and hepatic lipogenesis. [21] [22]

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 physical exercise. [37]

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). [38]

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). [39] These cytokines are commonly referred to as the IL-6 like or gp130 utilising cytokines [40]

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, [41] [42] [43] glycoprotein 130, [44] and Galectin-3. [45]

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 multiple sclerosis, [46] neuromyelitis optica spectrum disorder (NMOSD), [46] diabetes, [47] atherosclerosis, [48] gastric cancer, [49] depression, [50] Alzheimer's disease, [51] systemic lupus erythematosus, [52] multiple myeloma, [53] prostate cancer, [54] Behçet's disease, [55] rheumatoid arthritis, [56] and intracerebral hemorrhage. [57]

Hence, there is an interest in developing anti-IL-6 agents as therapy against many of these diseases. [58] [59] The first such is tocilizumab, which has been approved for rheumatoid arthritis, [60] Castleman's disease [61] and systemic juvenile idiopathic arthritis. [62] Others are in clinical trials. [63] It has been observed that genetic inactivation of ZCCHC 6 suppresses IL‐6 expression and reduces the severity of experimental osteoarthritis in Mice. [64] Some plant derived small molecule such as Butein have been reported to inhibit IL-6 expression in IL-1β stimulated human chondrocytes. [65]

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, [66] 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. [67] [68] [69] [70] [71] 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. [71]

Rheumatoid arthritis

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

Cancer

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. [72] [73] [74] IL-6 was seen to have roles in tumor microenvironment regulation, [75] [74] production of breast cancer stem cell-like cells, [76] metastasis through down-regulation of E-cadherin, [77] and alteration of DNA methylation in oral cancer. [78]

Advanced/metastatic cancer patients have higher levels of IL-6 in their blood. [79] One example of this is pancreatic cancer, with noted elevation of IL-6 present in patients correlating with poor survival rates. [80]

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. [81] [82] 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). [83] This phosphorylation causes movement of DNMT1 to the nucleus, where it can be transcribed. [83] DNMT1 recruits other DNMTs, including DNMT3A and DNMT3B, which, as a complex, recruit HDAC1. [82] 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. [82] Increased IL-6, therefore, can hypermethylate DNA sequences and subsequently decrease gene expression through its effects on DNMT1 expression. [84]

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. [82] This hypermethylation may potentially lead to the decreased GAD67 levels seen in the brains of people with schizophrenia. [85] GAD67 may be involved in the pathology of schizophrenia through its effect on GABA levels and on neural oscillations. [86] 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. [86] These neural oscillations are impaired in schizophrenia, and these alterations may be responsible for both positive and negative symptoms of schizophrenia. [87]

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). [88] [89] 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). [90] [88] IL-6 and IL-8 are the most conserved and robust features of SASP. [91]

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. [74]

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. [92] Altered BDNF function has been implicated in depression, [93] which is likely due to epigenetic modification following IL-6 upregulation. [92] BDNF is a neurotrophic factor implicated in spine formation, density, and morphology on neurons. [94] 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. [95] The anterior cingulate cortex is responsible for detecting incongruences between expectation and perceived experience. [96] Altered connectivity of the anterior cingulate cortex in depression, therefore, may cause altered emotions following certain experiences, leading to depressive reactions. [96] This altered connectivity is mediated by IL-6 and its effect on epigenetic regulation of BDNF. [92]

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. [97] This is of key interest as: 1) a meta-analysis indicates an association of major depressive disorder, C-reactive protein and IL6 plasma concentrations, [98] 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. [99] [100] (see Summary of NK1RAs in Major Depression), 3) the preliminary observation that plasma concentrations of IL6 are elevated in depressed patients with cancer, [101] and 4) selective NK1RAs may eliminate endogenous SP stress-induced augmentation of IL-6 secretion pre-clinically. [102] 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 underwent clinical trials for adjunctive treatment of major depressive disorder in 2015–2018, [103] but this research has been discontinued. [104]

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. [105]

Protein superfamily

Interleukin is the main member of the IL-6 superfamily (Pfam PF00489), which also includes G-CSF, IL23A, and CLCF1. A viral version of IL6 is found in Kaposi's sarcoma-associated herpesvirus. [106]

See also

Related Research Articles

In immunology, cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome (SIRS) that can be triggered by a variety of factors such as infections and certain drugs. It refers to cytokine storm syndromes (CSS) and occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody medications, as well as adoptive T-cell therapies. When occurring as a result of a medication, it is also known as an infusion reaction.

<span class="mw-page-title-main">Interleukin 10</span> Anti-inflammatory cytokine

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

<span class="mw-page-title-main">Interleukin 8</span> Mammalian protein found in humans

Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel–Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.

<span class="mw-page-title-main">Oncostatin M</span> Mammalian protein found in Homo sapiens

Oncostatin M, also known as OSM, is a protein that in humans is encoded by the OSM gene.

<span class="mw-page-title-main">Caspase 1</span> Enzyme found in humans

Caspase-1/Interleukin-1 converting enzyme (ICE) is an evolutionarily conserved enzyme that proteolytically cleaves other proteins, such as the precursors of the inflammatory cytokines interleukin 1β and interleukin 18 as well as the pyroptosis inducer Gasdermin D, into active mature peptides. It plays a central role in cell immunity as an inflammatory response initiator. Once activated through formation of an inflammasome complex, it initiates a proinflammatory response through the cleavage and thus activation of the two inflammatory cytokines, interleukin 1β (IL-1β) and interleukin 18 (IL-18) as well as pyroptosis, a programmed lytic cell death pathway, through cleavage of Gasdermin D. The two inflammatory cytokines activated by Caspase-1 are excreted from the cell to further induce the inflammatory response in neighboring cells.

<span class="mw-page-title-main">Interleukin 11</span> Protein-coding gene in the species Homo sapiens

Interleukin 11 is a protein that in humans is encoded by the IL11 gene.

<span class="mw-page-title-main">Interleukin 15</span> Cytokine with structural similarity to Interleukin-2

Interleukin-15 (IL-15) is a protein that in humans is encoded by the IL15 gene. IL-15 is an inflammatory cytokine with structural similarity to Interleukin-2 (IL-2). Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and the common gamma chain. IL-15 is secreted by mononuclear phagocytes following infection by virus(es). This cytokine induces the proliferation of natural killer cells, i.e. cells of the innate immune system whose principal role is to kill virally infected cells.

<span class="mw-page-title-main">Interleukin 31</span>

Interleukin-31 (IL-31) is a protein that in humans is encoded by the IL31 gene that resides on chromosome 12. IL-31 is an inflammatory cytokine that helps trigger cell-mediated immunity against pathogens. It has also been identified as a major player in a number of chronic inflammatory diseases, including atopic dermatitis.

<span class="mw-page-title-main">Interleukin 30</span> Protein-coding gene in the species Homo sapiens

Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3. The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.

<span class="mw-page-title-main">Interleukin 22</span> Protein, encoded in humans by IL22 gene

Interleukin-22 (IL-22) is a protein that in humans is encoded by the IL22 gene.

<span class="mw-page-title-main">Interleukin 20</span> Protein-coding gene in the species Homo sapiens

Interleukin 20 (IL20) is a protein that is in humans encoded by the IL20 gene which is located in close proximity to the IL-10 gene on the 1q32 chromosome. IL-20 is a part of an IL-20 subfamily which is a part of a larger IL-10 family.

<span class="mw-page-title-main">Glycoprotein 130</span> Mammalian protein found in Homo sapiens

Glycoprotein 130 is a transmembrane protein which is the founding member of the class of tall cytokine receptors. It forms one subunit of the type I cytokine receptor within the IL-6 receptor family. It is often referred to as the common gp130 subunit, and is important for signal transduction following cytokine engagement. As with other type I cytokine receptors, gp130 possesses a WSXWS amino acid motif that ensures correct protein folding and ligand binding. It interacts with Janus kinases to elicit an intracellular signal following receptor interaction with its ligand. Structurally, gp130 is composed of five fibronectin type-III domains and one immunoglobulin-like C2-type (immunoglobulin-like) domain in its extracellular portion.

<span class="mw-page-title-main">Interleukin-6 receptor</span> Protein-coding gene in the species Homo sapiens

Interleukin 6 receptor (IL6R) also known as CD126 is a type I cytokine receptor.

Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.

<span class="mw-page-title-main">SIGIRR</span> Protein-coding gene in the species Homo sapiens

Single Ig IL-1-related receptor (SIGIRR), also called Toll/Interleukin-1 receptor 8 (TIR8) or Interleukin-1 receptor 8 (IL-1R8), is transmembrane protein encoded by gene SIGIRR, which modulate inflammation, immune response, and tumorigenesis of colonic epithelial cells.

An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

Anti-interleukin-6 agents are a class of therapeutics. Interleukin 6 is a cytokine relevant to many inflammatory diseases and many cancers. Hence, anti-IL6 agents have been sought. In rheumatoid arthritis they can help patients unresponsive to TNF inhibitors.

A myokine is one of several hundred cytokines or other small proteins and proteoglycan peptides that are produced and released by skeletal muscle cells in response to muscular contractions. They have autocrine, paracrine and/or endocrine effects; their systemic effects occur at picomolar concentrations.

<span class="mw-page-title-main">Olamkicept</span> Chemical compound

Olamkicept, also known as soluble gp130Fc or sgp130Fc is an immunosuppressive drug candidate, which selectively blocks activities of the cytokine Interleukin-6, which are mediated by the soluble Interleukin-6. Interleukin-6 is a cytokine, which plays a dominant role in the regulation of the immune response and also in autoimmunity. Furthermore, Interleukin-6 has been demonstrated to be involved in the regulation of metabolism and body weight. Interleukin-6 also has many activities on neural cells. The biochemical principle was invented by the German biochemist Stefan Rose-John and it was further developed into a biotech compound by the Conaris Research Institute AG, which gave an exclusive world-wide license to the Swiss-based biopharmaceutical company Ferring Pharmaceuticals. In December 2016, Ferring and the biotech company I-MAB signed a licensing agreement granting I-MAB exclusive rights in Asia to Olamkicept for the treatment of autoimmune disease.

Hyper-IL-6 is a designer cytokine, which was generated by the German biochemist Stefan Rose-John. Hyper-IL-6 is a fusion protein of the four-helical cytokine Interleukin-6 and the soluble Interleukin-6 receptor which are covalently linked by a flexible peptide linker. Interleukin-6 on target cells binds to a membrane bound Interleukin-6 receptor. The complex of Interleukin-6 and the Interleukin-6 receptor associate with a second receptor protein called gp130, which dimerises and initiates intracellular signal transduction. Gp130 is expressed on all cells of the human body whereas the Interleukin-6 receptor is only found on few cells such as hepatocytes and some leukocytes. Neither Interleukin-6 nor the Interleukin-6 receptor have a measurable affinity for gp130. Therefore, cells, which only express gp130 but no Interleukin-6 receptor are not responsive to Interleukin-6. It was found, however, that the membrane-bound Interleukin-6 receptor can be cleaved from the cell membrane generating a soluble Interleukin-6 receptor. The soluble Interleukin-6 receptor can bind the ligand Interleukin-6 with similar affinity as the membrane-bound Interleukin-6 receptor and the complex of Interleukin-6 and the soluble Interleukin-6 receptor can bind to gp130 on cells, which only express gp130 but no Interleukin-6 receptor. The mode of signaling via the soluble Interleukin-6 receptor has been named Interleukin-6 trans-signaling whereas Interleukin-6 signaling via the membrane-bound Interleukin-6 receptor is referred to as Interleukin-6 classic signaling. Therefore, the generation of the soluble Interleukin-6 receptor enables cells to respond to Interleukin-6, which in the absence of soluble Interleukin-6 receptor would be completely unresponsive to the cytokine.

References

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