Interleukin 1

Interleukin-1 (IL-1) is a cytokine that is secreted by various cell types of the immune system such as macrophages, monocytes and dendritic cells, but also by fibroblasts and endothelial cells. It owes its name to the fact that it was the first cytokine to be discovered. The cytokine is produced in response to bacterial infections (its production is mainly mediated by LPS = important PAMP, which has been identified as an integral and essential component of the outer membrane of Gram-negative bacteria. The naming LPS = lipopolysaccharide refers to its chemical structure; it consists of a hydrophilic polysaccharide portion and a hydrophobic lipid A., an endotoxin of Gram-negative bacteria, stimulates).

Interleukin-1 has both local and general systemic effects, including the promotion of inflammatory processes in response to bacterial infections such as vasodilation, limb pain and fever. It also stimulates the production of prostaglandins by various cell types (muscles, epithelia, etc.), the production of other cytokines such as interleukin-2 and the activation and recruitment of other cells of the immune system. Specifically, interleukin-1 cytokines cause vasodilation of blood vessels (through prostaglandins), promoting the migration of immune cells such as macrophages and lymphocytes to the site of infection. IL-1 favors the expression of adhesion molecules in the cells of the endothelium of the blood vessels, the anchoring of leukocytes to the vessel walls and their migration into the tissue. Another ability of interleukin-1 cytokines is to contribute to the activation of T helper lymphocytes and to the maturation and clonal expansion of B lymphocytes. In systemic infections, the effect of interleukin-1 is comparable to TNF-alpha in that it stimulates the production of acute phase proteins in the liver.

In addition to stimulating inflammatory processes, interleukin-1 is able to trigger fever directly and autonomously even in the absence of other stimuli (bacterial antigens, see AMP - antimicrobialpeptides below) and is therefore referred to as an endogenous pyrogen . Interleukin-1 binds to specific receptors in the endothelial cells of the hypothalamus and appears to be able to "reset" its thermoregulation center. This leads to an increase in body temperature, a fever. Under febrile temperatures, the replication of bacteria and viruses decreases, while the immune response becomes more efficient.

Release of interleukin-1: DAMPs (DAMPs = acronym for "danger-associated molecular pattern", also known as alarmins are non-microbial pathogens that lead to the release of inflammatory mediators such as interleukin-1beta and interleukin-18 in the organism) or PAMPs (e.g. antimicrobial peptides) play a major role here. DAMPs/PAMPs are released by "stressed" cells, for example. Cell stress can be caused by infections but also by injuries, ischemia, hypoxia, acidosis and complement lysis. This results in necrosis or pyroptosis of the attacked cells. Intracellular components with damaged protein molecules enter the extracellular space. Due to their faulty structures (misfolding of proteins, oxidative changes in connection with the altered pH value), such pathological proteins are recognized by cells of innate immunity via their pattern recognition receptors (PRRs). They act as signaling devices for the immune system, which then reacts to them. A first step is the cleavage of the constitutively stored interleukin-1 alpha precursor molecule into its active form by a Ca2+-activated protease called calpain. The N-terminal 16 kDa cleavage product (ppIL-1 alpha) is cleaved and released. PpIL-1 alpha contains a nuclear localization sequence (NLS). This migrates into the cell nucleus and functions there as a transcription factor.

Inflammatory reactions without infection: Non-infectious inflammatory reactions, e.g. in ischemia, can also be initiated via the interleukin-1 receptor (IL-1R). IL-1 alpha stimulates the transcription and secretion of IL-1beta from monocytes. IL-1beta appears to be an amplifier of inflammation through the recruitment of macrophages and other inflammatory cells.

Interleukin-1: Interleukin-1 (IL-1) is highly expressed by tissue macrophages, monocytes, fibroblasts and dendritic cells, but also by B lymphocytes, NK cells, microglia and epithelial cells. The cytokines of the entire interleukin-1 family represent an important part of the body's general inflammatory reactions. Among other things, IL-1 binds to hypothalamic receptors and is thus able to directly alter the activity of the thermoregulation center of the hypothalamus in the sense of a fever reaction. Under hyperthermic conditions, the replication of bacteria and viruses decreases, while the immune response becomes more efficient. In this respect, interleukin-1 is also referred to as an endogenous pyrogen. IL-1 also causes increased sensitivity to pain, vasodilatation and hypotension.

So far, 2 variants of interleukin-1 have been identified:

• Interleukin-1 alpha (IL-1alpha)
• Interleukin-1beta (IL-1-beta)

Both IL-1 cytokine variants have analogous activities (bind to the same receptor/interleukin-1 receptor). However, they are structurally different. Both are synthesized as cytokine precursors (33 kDa) and are only converted into their active forms (approx. 17 kDa) after proteolytic processing.

Interleukin-1alpha: Interleukin-1 alpha is a "dual function cytokine", i.e. the cytokine acts both on the cell nucleus by influencing transcription, and extracellularly, as a classical cytokine. Interleukin-1 alpha is constitutively stored in the cytoplasm of cells of mesenchymal origin and in epithelial cells and is therefore immediately and locally available. Monocytes and macrophages do not produce "prefabricated" interleukin-1 alpha precursor proteins. They are therefore dependent on de novo synthesis when required.

In contrast to interleukin-1alpha,interleukin-1beta is only synthesized after stimulation! Its expression is induced by the transcription factor NF-κB after immune cells have been put into an activated state. This occurs, for example, through bacterial lipopolysaccharides (LPS) which are recognized as pathogen-associated molecular patterns(PAMPs) by macrophages and dendritic cells. Interleukin-1beta (like interleukin-1alpha) is also synthesized as a precursor protein. The synthesis of the interleukin-1beta precursor (this also applies to interleukin-18) is triggered by stimulation of cells of the innate immune system by Toll-like receptors (TLRs) or RIG-like receptors (RLRs). In order to achieve its actual biological function (= the ability to bind to the interleukin-1 receptor), the interleukin-1-beta precursor must be cleaved by the cysteine protease caspase-1. The caspase-1 enzyme is activated by special protein formations (inflammasomes) (inflammasomes are cytosolic/intracellular multi-protein complexes that occur predominantly in immune cells, such as dendritic cells and macrophages, but above all also in the epithelia of the skin and mucous membranes. Inflammasomes can also trigger a special form of programmed cell death, PANOptosis). Under certain circumstances, interleukin-1beta can also be processed by other proteases, e.g. in the case of severe neutrophilic inflammation.

The other interleukins listed here belong to the extended interleukin family.

• Interleukin-18: Interleukin-18 (IL-18) is a cytokine that stimulates the production of interferon gamma (IFN-γ). Like interleukin-1 beta, interleukin-18 is synthesized as a precursor and cleaved by caspase-1. Interleukin-18 is a proinflammatory cytokine that has similar biological effects to interleukin-12 (IL-12). However, it shares structural forms with the interleukin-1 family. Together with interleukin-12, it mediates cellular immunity. IL-18 binds to the IL-18Rα receptor and is produced by monocytes, macrophages, osteoblasts and keratinocytes. IL-18 stimulates IFN-gamma production by T cells and NK cells. It acts either independently or in synergy with interleukin-12, which can lead to rapid activation of the monocyte/macrophage system. Synergy with interleukin-12 inhibits IL-4-dependent production of IgE and IgG1, but promotes IgG2 production by B cells. In addition to these regulatory physiological functions, interleukin-18 is involved in several severe inflammatory reactions. IL-18 is also elevated in Hashimoto's thyroiditis. Furthermore, interleukin-18 has been shown to increase beta-amyloid production in neurons in Alzheimer's disease.
• Interleukin 1 receptor accessory protein (IL-1RAcP): The accessory protein of the interleukin-1 receptor belongs to the immunoglobulin superfamily of proteins and consists of soluble and membranous isoforms. IL-1RAcP plays an essential role in the signaling of IL-1 family cytokines such as IL-1, IL-33 and IL-36. IL-1RAcP generally initiates the inflammatory signaling pathway by recruiting signaling mediators, including MYD88 and IRAK. Chronic inflammation following sustained cytokine receptor signaling is a critical process in the pathogenesis of many inflammatory diseases, including autoimmunity, obesity, psoriasis, type 1 diabetes, endometriosis, preeclampsia, and Alzheimer's disease. Targeting the IL-1RAcP signaling pathway also suggests its potential as a therapeutic target for inflammatory and autoimmune diseases. To date, four isoforms of IL-1RAcP have been identified.
• Interleukin-1 receptor antagonist (IL-1RA): IL-1RA is the first naturally occurring receptor antagonist of a cytokine to be described. The receptor antagonist shares 52% amino acid sequence homology with the interleukin-36 receptor antagonist (IL-36RA). IL-1RA proves its membership of the interleukin-1 cytokine family by three criteria:
• -Amino acid sequence homology of 26 to 30 % to interleukin-1beta and 19 % to interleukin-1alpha.
• -similarities in the gene structure
• -Common gene localization on chromosome 2q14.
• The interleukin-1 receptor antagonist is produced by monocytes, macrophages, neutrophils, fibroblasts, epithelial cells, Sertoli cells and microglia. IL-1RA is synthesized as a preprotein. Several variants of the interleukin-1 receptor antagonist have been identified: the 17 kDa form, called sIL-1ra (s = soluble/ is also known as IL-1ra1). This form contains the classical signal sequence and is a secreted form of IL-1ra. The other two forms (icIL-1ra/IL-1ra2 and IL-1ra3) have no signal sequence. They are not secreted and remain strictly intercellular. The soluble form is produced by hepatocytes and regulated by proinflammatory cytokines (interleukin-1beta and a combination of interleukin-1beta and interleukin-6) and other acute phase proteins. The interleukin-1 receptor antagonist has been detected in fibroblasts, monocytes, neutrophils, keratinocytes and bronchial epithelial cells. It is an important regulator of IL-1-induced expression and IL-1-induced biological responses. In vivo and in vitro, it acts as a competitive inhibitor of the interleukin-1 receptor and inhibits the effects of both IL-1alpha and IL-1beta. The interleukin-1 receptor antagonist blocks the stimulation of prostaglandin E2 synthesis in synovial cells and thymocyte proliferation. It also inhibits the release of leukotriene B4 from monocytes after stimulation with bacterial lipopolysaccharides and blocks insulin release from isolated pancreatic cells. A polymorphism of the coding gene is associated with an increased risk of osteoporotic fractures as well as(DIRA) a rare congenital disease with severe pustular skin and bone inflammation. The interleukin-1 receptor antagonist is produced commercially as a recombinant form of IL-1ra(Anakinra).
• Interleukin-33: IL-33 is synthesized as a 31-kDa precursor form and binds to the ST2 receptor and the IL-1RAcP coreceptor, stimulating signal transduction that activates transcription factors such as NF-κB and ERK, p38 and JNK MAPKs. Signaling can be triggered by a precursor form of interleukin-33 in the same way that the interleukin-1alpha precursor activates signaling through the interleukin-1 receptor. The mature forms of interleukin-33 (IL-3395-270, IL-3399-270 and IL-33109-270), which are processed from a precursor by the serine proteases cathepsin G and elastase, are even more potent activators of inflammatory reactions. In contrast to interleukin-1, processing by caspases, such as caspase-1, leads to the inactivation of interleukin-33 (Sutinen EM et al. 2012; Lefrançais E et al. 2012). Like other cytokines of the interleukin-1 family, interleukin-33 is a cytokine with a dual function. In addition to its chromatin-associated function, it is constitutively expressed in endothelial cells as it acts as DAMP after its release into the extracellular space of cells in the context of immunologic non-silent cell death (necrosis or pyroptosis) and drives cytokine production in natural helper cells, Th2 lymphocytes, mast cells, basophils, eosinophils, natural killer and natural killer T cells. Interleukin-33 is involved in allergic and parasite-induced inflammatory responses (Lefrançais E et al. 2012).
• Interleukin-36: IL-36 is present in 3 variants:
• -Interleukin-36 alpha(IL-36alpha) is expressed in spleen, lymph nodes, tonsils , bone marrow and B cells. This member is unique in that it is also synthesized by T lymphocytes. It is closely related to interleukin-37 and interleukin-36 beta.
• -Interleukin-36beta (IL-36 beta) is expressed in tonsils, bone marrow, heart, placenta, lung, testis, intestine, monocytes and B lymphocytes. It is most similar to interleukin-36alpha. Two alternative transcripts encoding the same protein have been described (Debets R et al. 2001).
• -Interleukin-36 gamma (IL-36 gamma) is mainly produced by keratinocytes. It activates NF-κB via IL-1Rrp2 and is specifically inhibited by interleukin-36 ra (Kumar S et al. 2000]. Its production increases after IL-1beta and TNF-α stimulation, but not after IL-18 or IFN-γ stimulation. IL-36gamma plays an important role in skin immunity and inflammation. Expression is increased in chronic contact hypersensitivity, herpes simplex virus infection and psoriasis.
• Interleukin-36 receptor antagonist (IL-36ra ) is highly expressed by keratinocytes, in psoriatic skin, placenta, uterus, brain, kidneys, monocytes, B lymphocytes and dendritic cells. Interleukin-36 ra is 155 amino acids long and has no signal sequence. The receptor antagonist has a 52% homology in the amino acid sequence with the interleukin-1 receptor antagonist(IL-1 ra). IL-36 ra acts as a non-specific inhibitor of inflammation and innate immunity. It inhibits NF-κB activation induced by IL-36alpha (Kumar S et al. 2002). LOF mutations in the coding gene lead to DITRA, the interleukin-36 receptor antagonist deficiency syndrome of a severe pustular systemic disease.
• Interleukin-37 (IL-37) is expressed in most tissues. It is the first member of the IL-1 family to form homodimers.[43] IL-37 non-specifically inhibits the inflammatory response and innate immunity. IL-37 (IL-1F7) has also been found in the cell nucleus, where it can act as a nuclear factor. This cytokine can bind to the IL-18 receptor (IL18R1 / IL-1Rrp). It also binds to the interleukin-18 binding protein (IL18BP) and forms a complex with the beta subunit of the IL-18 receptor (IL-1F4), thereby inhibiting its activity. Five alternative transcripts encoding different IL-37 isoforms have been described.
• Interleukin-38 (IL-38) is expressed both in the skin and in the tonsils. It regulates both innate and adaptive immunity. It binds to the soluble IL-1RI receptor. Two alternative transcripts encoding the same protein have been described.

• Interleukin-1: Interleukin-1 (IL-1) is highly expressed by tissue macrophages, monocytes, fibroblasts and dendritic cells, but also by B lymphocytes, NK cells, microglia and, particularly important from a dermatological point of view, by epithelial cells. The cytokines of the interleukin-1 family form an important part of the body's general inflammatory response to infections. The interleukin-1 cytokines increase the expression of adhesion factors on endothelial cells to enable the transmigration (diapedesis) of immunocompetent cells such as phagocytes, lymphocytes and others to sites of infection. IL-1 binds to receptors in the endothelial cells of the hypothalamus and is thus able to directly alter the activity of the thermoregulation center of the hypothalamus and induce an increase in body temperature (fever). Under these hyperthermic conditions, the replication of bacteria and viruses decreases, while the immune response becomes more efficient. In this respect, intereluekin-1 is also referred to as an endogenous pyrogen. IL-1 also causes increased sensitivity to pain, vasodilation and hypotension. So far, 2 variants of interleukin-1 have been identified:
  • Interleukin-1 alpha (IL-1alpha)
  • Interleukin-1beta (IL-1-beta)
  • Both IL-1 cytokine variants have analogous activities (bind to the same receptor). However, they are structurally different. Both are synthesized as cytokine precursors (33 kDa) and are only converted into their active forms (approx. 17 kDa) after proteolytic processing. Both interleukin-1alpha and interleukin-1beta act on the same receptor(interleukin-1 receptor).
• Interleukin-1 alpha: Interleukin-1 alpha is a"dual function cytokine", i.e. the cytokine acts both on the cell nucleus by influencing transcription, and extracellularly, as a classical cytokine. Interleukin-1 alpha is constitutively stored in the cytoplasm of cells of mesenchymal origin and in epithelial cells and is therefore immediately and locally available. Monocytes and macrophages do not produce "prefabricated" interleukin-1 alpha precursor proteins. They are therefore dependent on de novo synthesis when required.
• In contrast to interleukin-1alpha,interleukin-1beta is only synthesized after stimulation! Its expression is induced by the transcription factor NF-κB after immune cells have been put into an activated state. This occurs, for example, through bacterial lipopolysaccharides (LPS) which are recognized as pathogen-associated molecular patterns(PAMPs) by macrophages and dendritic cells. Interleukin-1beta (like interleukin-1alpha) is synthesized as a precursor protein. The synthesis of the interleukin-1beta precursor (this also applies to interleukin-18) is triggered by stimulation of cells of the innate immune system by Toll-like receptors (TLRs) or RIG-like receptors (RLRs). In order to achieve its actual biological function (= the ability to bind to the interleukin-1 receptor), the interleukin-1-beta precursor must be cleaved by the cysteine protease caspase-1. The caspase-1 enzyme is activated by special protein formations(inflammasomes) (inflammasomes are cytosolic/intracellular multi-protein complexes that occur predominantly in immune cells, such as dendritic cells and macrophages, but above all also in the epithelia of the skin and mucous membranes. Inflammasomes can also trigger a special form of programmed cell death, PANOptosis). Under special circumstances, interleukin-1beta can also be processed by other proteases, e.g. in the case of severe neutrophilic inflammation.
• Interleukin-18: Interleukin-18 (IL-18) is a cytokine that stimulates the production of interferon gamma (IFN-γ). Like interleukin-1 beta, interleukin-18 is synthesized as a precursor and cleaved by caspase-1. Interleukin-18 is a proinflammatory cytokine that has similar biological effects to interleukin-12 (IL-12). However, it shares structural forms with the interleukin-1 family. Together with interleukin-12, it mediates cellular immunity. IL-18 binds specifically to the IL-18Rα receptor and is produced by monocytes, macrophages, osteoblasts and keratinocytes. IL-18 stimulates IFN-gamma production by T cells and NK cells. It acts either independently or in synergy with interleukin-12, which can lead to rapid activation of the monocyte/macrophage system. Synergy with interleukin-12 inhibits IL-4-dependent production of IgE and IgG1, but promotes IgG2 production by B cells. In addition to these regulatory physiological functions, interleukin-18 is involved in several severe inflammatory reactions. IL-18 is also elevated in Hashimoto's thyroiditis. Furthermore, interleukin-18 has been shown to increase beta-amyloid production in neurons in Alzheimer's disease.
• Interleukin 1 receptor accessory protein (IL-1RAcP): The accessory protein of the interleukin-1 receptor belongs to the immunoglobulin superfamily of proteins and consists of soluble and membranous isoforms. IL-1RAcP plays an essential role in the signaling of IL-1 family cytokines such as IL-1, IL-33 and IL-36. IL-1RAcP generally initiates the inflammatory signaling pathway by recruiting signaling mediators, including MYD88 and IRAK. Chronic inflammation following sustained cytokine receptor signaling is a critical process in the pathogenesis of many inflammatory diseases, including autoimmunity, obesity, psoriasis, type 1 diabetes, endometriosis, preeclampsia, and Alzheimer's disease. Targeting the IL-1RAcP signaling pathway also suggests its potential as a therapeutic target for inflammatory and autoimmune diseases. To date, four isoforms of IL-1RAcP have been identified.
• Interleukin-1 receptor antagonist (IL-1RA): IL-1RA is the first naturally occurring receptor antagonist of a cytokine to be described. IL-1RA demonstrates its membership of the interleukin-1 cytokine family by three criteria:
  • Amino acid sequence homology of 26 to 30 % to interleukin-1beta and 19 % to interleukin-1alpha.
  • Similarities in the gene structure
  • common gene localization on chromosome 2q14.
• The interleukin-1 receptor antagonist is produced by monocytes, macrophages, neutrophils, fibroblasts, epithelial cells, Sertoli cells and microglia. IL-1RA is synthesized as a preprotein. Several variants of the interleukin-1 receptor antagonist have been identified: the 17 kDa form, called sIL-1ra (s = soluble/ is also known as IL-1ra1). This form contains the classical signal sequence and is a secreted form of IL-1ra. The other two forms (icIL-1ra/IL-1ra2 and IL-1ra3) have no signal sequence. They are not secreted and remain strictly intercellular. The soluble form is produced by hepatocytes and regulated by proinflammatory cytokines (interleukin-1beta and a combination of interleukin-1beta and interleukin-6) and other acute phase proteins. The interleukin-1 receptor antagonist has been detected in fibroblasts, monocytes, neutrophils, keratinocytes and bronchial epithelial cells. It is an important regulator of IL-1-induced expression and IL-1-induced biological responses. In vivo and in vitro, it acts as a competitive inhibitor of the interleukin-1 receptor and inhibits the effects of both IL-1alpha and IL-1beta. The interleukin-1 receptor antagonist blocks the stimulation of prostaglandin E2 synthesis in synovial cells and thymocyte proliferation. It also inhibits the release of leukotriene B4 from monocytes after stimulation with bacterial lipopolysaccharides and blocks insulin release from isolated pancreatic cells. A polymorphism of the coding gene is associated with an increased risk of osteoporotic fractures as well as (DIRA) a rare congenital disease with severe pustular skin and bone inflammation. The interleukin-1 receptor antagonist is produced commercially as a recombinant form of IL-1ra (Anakinra).
• Interleukin-33: IL-33 is synthesized as a 31-kDa precursor form and binds to the ST2 receptor and the IL-1RAcP coreceptor, stimulating signal transduction that activates transcription factors such as NF-κB and ERK, p38 and JNK MAPKs. Signaling can be triggered by a precursor form of interleukin-33 in the same way that the interleukin-1alpha precursor activates signaling through the interleukin-1 receptor. The mature forms of interleukin-33 (IL-3395-270, IL-3399-270 and IL-33109-270), which are processed from a precursor by the serine proteases cathepsin G and elastase, are even more potent activators of inflammatory reactions. In contrast to interleukin-1, processing by caspases, such as caspase-1, leads to the inactivation of interleukin-33 (Sutinen EM et al. 2012; Lefrançais E et al. 2012). Like other cytokines of the interleukin-1 family, interleukin-33 is a cytokine with a dual function. In addition to its chromatin-associated function, it is constitutively expressed in endothelial cells as it acts as DAMP after its release into the extracellular space of cells in the context of immunologic non-silent cell death (necrosis or pyroptosis) and drives cytokine production in natural helper cells, Th2 lymphocytes, mast cells, basophils, eosinophils, natural killer and natural killer T cells. Interleukin-33 is involved in allergic and parasite-induced inflammatory responses (Lefrançais E et al. 2012).
• Interleukin-33 plays a role in the so-called cytokine-induced effector cytokine production. This mechanism causes the cytokine-dependent production of effector cytokines by differentiated T helper lymphocytes without antigen stimulation by the T cell receptor of these cells. Interleukin-33 can thus increase the expression of its own receptor on already differentiated Th2 lymphocytes in combination with some STAT5 activators such as IL-2, IL-7. This upregulation acts like a positive feedback loop, and thus an even stronger activation of IL-33-dependent signaling pathways in lymphocytes.
• Interleukin-36 alpha: Interleukin-36 alpha(IL-36alpha) is expressed in spleen, lymph nodes, tonsils, bone marrow and B cells. This member is unique in that it is also synthesized by T lymphocytes. It is closely related to interleukin-37 and interleukin-36 beta.
• Interleukin-36beta (IL-36 beta) is expressed in tonsils, bone marrow, heart, placenta, lung, testis, intestine, monocytes and B lymphocytes. It is most similar to interleukin-36alpha. Two alternative transcripts encoding the same protein have been described (Debets R et al. 2001).
• Interleukin-36 gamma (IL-36 gamma) is mainly produced by keratinocytes. It activates NF-κB via interleukin-1 receptor-like 2 (IL-1Rrp2) and is specifically inhibited by interleukin-36 ra (Kumar S et al. 2000]. Its production increases after IL-1beta and TNF-α stimulation, but not after IL-18 or IFN-γ stimulation. IL-36gamma plays an important role in skin immunity and inflammation. Expression is increased in chronic contact hypersensitivity, herpes simplex virus infection and psoriasis.
• Interleukin-36 ra (IL-36ra ) is highly expressed by keratinocytes, in psoriatic skin, placenta, uterus, brain, kidneys, monocytes, B lymphocytes and dendritic cells. Interleukin-36 ra is 155 amino acids long and has no signal sequence. The receptor antagonist has a 52% homology with interleukin-1 ra in the amino acid sequence. Interleukin-36 ra acts as a non-specific inhibitor of inflammation and innate immunity. It inhibits NF-κB activation induced by IL-36α (Kumar S et al. (2002).
• Interleukin-37 (IL-37) is expressed in most tissues. It is the first member of the IL-1 family to form homodimers .[43] IL-37 non-specifically inhibits the inflammatory response and innate immunity. IL-37 (IL-1F7) has also been found in the cell nucleus, where it can act as a nuclear factor. This cytokine can bind to the IL-18 receptor (IL18R1 / IL-1Rrp) or be a ligand of this receptor itself. It binds to the interleukin-18 binding protein (IL18BP) and forms a complex with the beta subunit of the IL-18 receptor (IL-1F4), thereby inhibiting its activity. Five alternative transcripts encoding different IL-37 isoforms have been described.
• Interleukin-38 (IL-38) is expressed both in the skin and in the tonsils. It regulates both innate and adaptive immunity. It binds to the soluble IL-1RI receptor. Two alternative transcripts encoding the same protein have been described.

IL-1 in disease and its clinical significance:

• IL-1 plays an important role in neuroinflammation, etc. During inflammation, increased levels of TNF and IL-1 occur in the brain, and their presence can lead to breakdown of the blood-brain barrier. Polymorphisms in IL-1 genes have been found to contribute to genetic susceptibility to some cancers, ankylosing spondylitis and Graves' disease (Durães C et al. 2014;Timms AE et al. 2004; Liu N et al. 2010).
• Blocking IL-1 activity, especially interleukin-1beta, is now a standard therapy for patients with autoimmune diseases or lymphomas. Anakinra (IL-1Ra) is approved by the FDA as a therapy for patients with rheumatoid arthritis. It has also been used in patients with indolent myeloma.

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