This article's lead section may be too short to adequately summarize the key points. (December 2019) |
The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.
Interleukin-1 / 18 | |||||||||
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Identifiers | |||||||||
Symbol | IL1 | ||||||||
Pfam | PF00340 | ||||||||
InterPro | IPR000975 | ||||||||
PROSITE | PDOC00226 | ||||||||
SCOP2 | 1i1b / SCOPe / SUPFAM | ||||||||
|
Discovery edit
Discovery of these cytokines began with studies on the pathogenesis of fever. The studies were performed by Eli Menkin and Paul Beeson in 1943–1948 on the fever-producing properties of proteins released from rabbit peritoneal exudate cells. These studies were followed by contributions of several investigators, who were primarily interested in the link between fever and infection/inflammation.[1] The basis for the term "interleukin" was to streamline the growing number of biological properties attributed to soluble factors from macrophages and lymphocytes. IL-1 was the name given to the macrophage product, whereas IL-2 was used to define the lymphocyte product. At the time of the assignment of these names, there was no amino acid sequence analysis known and the terms were used to define biological properties.
In 1985 two distinct, but distantly related complementary DNAs encoding proteins sharing human IL-1 activity were reported to be isolated from a macrophage cDNA library, thus defining two individual members of the IL-1 family – IL-1
The Interleukin-1 superfamily edit
IL-1 family is a group of 11 cytokines, which induces a complex network of proinflammatory cytokines and via expression of integrins on leukocytes and endothelial cells, regulates and initiates inflammatory responses.[5][6]
IL-1
Nine IL-1 superfamily members occur in a single cluster on human chromosome two; sequence and chromosomal anatomy evidence suggest these formed through a series of gene duplications of a proto-IL-1
Synthesis edit
All of the members of IL-1 family, except IL-1Ra, are first synthesized as a precursor protein, which means it is synthesized as a long form of a protein which has to be proteolytically cleaved to a shorter, active molecule, which is generally called a mature protein. IL-1 family precursors do not have a clear signal peptide for processing and secretion and none of them are found in the Golgi; they belong to so-called leaderless secretory protein group. The similar feature of IL-1
Nomenclature edit
The interleukin-1 superfamily has 11 members, which have similar gene structure, although originally it contained only four members IL-1
But according to new trends in nomenclature, the old names of IL-1 family returned. In 2010, laboratories all around the world agreed that IL-1
Name | Family name | Receptor | Coreceptor | Property | Chromosomal location |
---|---|---|---|---|---|
IL-1 |
IL-1F1 | IL-1RI | IL-1RAcP | Proinflammatory | 2q14.1 |
IL-1 |
IL-1F2 | IL-1RI | IL-1RAcP | Proinflammatory | 2q14.1 |
IL-1Ra | IL-1F3 | IL-1RI | NA | Antagonist for IL-1 |
2q14.1 |
IL-18 | IL-1F4 | IL-18R |
IL-18R |
Proinflammatory | 11q23.1 |
IL-36Ra | IL-1F5 | IL-1Rrp2 | NA | Antagonist for IL-36 |
2q14.1 |
IL-36 |
IL-1F6 | IL-1Rrp2 | IL-1RAcP | Proinflammatory | 2q14.1 |
IL-37 | IL-1F7 | Unknown | Unknown | Anti-inflammatory | 2q14.1 |
IL-36 |
IL-1F8 | IL-1Rrp2 | IL-1RAcP | Proinflammatory | 2q14.1 |
IL-36 |
IL-1F9 | IL-1Rrp2 | IL-1RAcP | Proinflammatory | 2q14.1 |
IL-38 | IL-1F10 | IL-1Rrp2 | Unknown | Anti-inflammatory | 2q14.1 |
IL-33 | IL-1F11 | ST2 | IL-1RAcP | Th2 responses, proinflammatory | 9p24.1 |
Signaling edit
IL-1
IL-1
After the formation of receptor heterodimeric complex which is assembled by IL-1
IL-1
Biological activity edit
IL-1 is intensely produced by tissue macrophages, monocytes, fibroblasts, and dendritic cells, but is also expressed by B lymphocytes, NK cells, microglia, and epithelial cells. They form an important part of the inflammatory response of the body against infection. These cytokines increase the expression of adhesion factors on endothelial cells to enable transmigration (also called diapedesis) of immunocompetent cells, such as phagocytes, lymphocytes and others, to sites of infection. They also affect the activity of the hypothalamus, the thermoregulatory center, which leads to a rise in body temperature (fever). That is why IL-1 is called an endogenous pyrogen. Besides fever, IL-1 also causes hyperalgesia (increased pain sensitivity), vasodilation and hypotension.[18]
IL-1α
edit
IL-1
IL-1
Inflammatory responses in the absence of infection (such as ischemia) are only dependent on IL-1
IL-1β
edit
IL-1
The synthesis of IL-1
IL-18 is also synthesized as a precursor which is cleaved by caspase-1.[18]
There are indications that IL-1, not least IL-1beta, is of importance for regulation energy metabolism. For instance, Rothwell and coworkers reported evidence that Leptin actions on food intake and body temperature are mediated by IL-1 at the level of the CNS (Luheshi GN, Gardner JD, Rushforth DA, Loudon AS, Rothwell NJ: Leptin actions on food intake and body temperature are mediated by IL-1. Proc Natl Acad Sci U S A 96:7047–7052, 1999). Moreover, lack of IL-1RI–mediated biological activity in IL-1 receptor knockout mice causes mature-onset obesity (Garcia M, Wernstedt I, Berndtsson A, Enge M, Bell M, Hultgren O, Horn M, Ahren B, Enerbäck S, Ohlsson C, Wallenius V, Jansson J-O. 2006. Mature onset obesity in interleukin-1 receptor I (IL-1RI) knockout mice. Diabetes, 55:1205-1213). A similar mature onset obesity has also been observed in IL-6 knockout mice (Wallenius V, Wallenius K, Ahrén B, Rudling M, Dickson SL, Ohlsson C, Jansson J-O. 2002 Interleukin-6 deficient mice develop mature-onset obesity. Nature Medicine 8:75-79). There are fewer reports on the effects on obesity by TNFalpha, the third classic proinflammatory cytokine, although Spiegelman and co-workers found that it has profound affects on glucose metabolism Gokhan S Hotamisligil, Narinder S Shargill, Bruce M. Spiegelman. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 01 Jan 1993: Vol. 259, Issue 5091, pp. 87–91DOI: 10.1126/science.7678183).
IL-1ra edit
IL-1ra is produced by monocytes, macrophages, neutrophils, fibroblasts, epithelial cells, Sertoli cells, microglia. IL-1ra is synthesized as a preprotein containing a classical 25 amino acid long signal sequence that allows secretion via the endoplasmic reticulum / Golgi apparatus. Mouse, rat and rabbit IL-1ra show 77, 75, and 78% sequence homology to human IL-1ra.[23] L-1ra shows approximately 30% homology to IL-1
Polymorphism of this gene is associated with an increased risk of osteoporotic fractures.[26] IL-1ra antagonist deficiency (DIRA) is a rare congenital disease. Affected children experience severe skin and bone inflammation, other organs such as the lungs may be affected.[27] IL-1ra is used in the treatment of rheumatoid arthritis. It is commercially produced as a recombinant form of IL-1ra and is called anakinra.
IL-18 edit
IL-18 is known as a factor that induces the production of interferon gamma (IFN-
IL-33 edit
IL-33 is synthesized as a 31-kDa precursor form and binds the ST2 receptor and IL-1RAcP coreceptor, which stimulates signaling that activates transcription factors as NF-
IL-33 is a dual function cytokine. Besides its chromatin-associated function, it is constitutively expressed in healthy endothelial cells, because it acts as DAMPs after its release to extracellular space of cells in the context of immunologic not-silent cell death (necrosis or pyroptosis), and drives cytokine production in natural helper cells, nuocytes, Th2 lymphocytes, mast cells, basophils, eosinophils, invariant natural killer and natural killer T cells. It is involved in allergic and parasite-induced inflammatory responses.[35][36]
IL-36α
edit
IL-36
IL-36β
edit
IL-36
IL-36γ
edit
IL-36
IL-36ra edit
IL-36ra is highly expressed by keratinocytes, in psoriatic skin, placenta, uterus, brain, kidneys, monocytes, B-lymphocytes and dendritic cells. IL-36ra is 155 amino acids long and lacks a signal sequence. IL-36ra shares with IL-1ra 52% homology in the amino acid sequence. IL-36ra acts as a non-specific inhibitor of inflammation and innate immunity. It inhibits IL-36
IL-37 edit
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-1F7 has also been found in the nucleus where it can function as a nuclear factor. This cytokine may bind or may itself be a ligand of the IL-18 receptor (IL18R1 / IL-1Rrp). It binds to the interleukin 18 binding protein (IL18BP), forming a complex with the beta subunit of the IL-18 receptor (IL-1F4), thereby inhibiting its activity. 5 alternative transcripts encoding different IL-37 isoforms have been described.[44]
IL-38 edit
IL-38 is expressed in the skin as well as 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.[45]
Cytokine-induced effector cytokine production edit
IL-33 has a role in so called cytokine-induced effector cytokine production, which means that a production of effector cytokines by differentiated T helper lymphocytes is cytokine dependent and can happen without antigen stimulation by T-cell receptor of these cells. IL-33 in combination with some STAT5 activators, such as IL-2, IL-7 or TSLP, up-regulates expression of its own receptor on already differentiated Th2 lymphocytes, because naive T helper cells nor Th1 nor Th17 populations do not have ST2 receptors. This up-regulation works as a positive feedback which causes even more strong activation of IL-33 dependent-signaling pathways in the lymphocyte. This up-regulation is directly controlled by GATA3 transcription factor. IL-33 combined with IL-2, IL-7 or TSLP also stimulates cell proliferation. The effector cytokine which is secreted from IL-33- and STAT5 activator-stimulated Th2 cells is IL-13, which is NF-
Similar functions have IL-1 to Th17 cells and IL-18 to Th1 lymphocytes. IL-1 combined with some STAT3 activators, such as IL-6, IL-21 or IL-23, which are important for Th17 lymphocytes differentiation, have similar positive feedback in Th17 cells just like IL-33 and STAT5 activators have in Th2 cells. They highly up-regulate expression of IL-1 receptor and ROR
IL-1 in disease and its clinical significance edit
IL-1 has a major role in neuroinflammation.[47] During inflammation, there are increased levels of TNF and IL-1 in the brain,[48][49] and their presence may cause the breakdown of the blood-brain barrier.[48] Polymorphisms in IL-1 genes have been found to contribute to genetic susceptibility to some cancers,[50] ankylosing spondylitis,[51] and Graves' disease.[52]
In terms of clinical use, because of its characterization as a hematopoietic factor, IL-1 was given to patients after bone marrow transplantation to improve the engraftment. But soon[when?] it was discovered that the patients were experiencing symptoms of systemic inflammation. Pharmacological blockade of these receptors was then sought in order to relieve symptoms. The endogenous IL-1 receptor antagonist (IL-1Ra), also known as anakinra, was tried in clinical trials to lessen systemic inflammation, but did not demonstrate a statistically significant difference from placebo.[5]
Nowadays, the blockade of IL-1 activity (especially IL-1
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