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Members of very wide interleukin-1 receptor (IL-1R) family are characterized by extracellular immunoglobulin-like domains and intracellular Toll/Interleukin-1R (TIR) domain. It is a group of structually homologous proteins, conserved throughout the species as it was identified from plants to mammals. Proteins of this family play important role in host defence, injury and stress [1] There are four main groups of TIR domain-containing proteins in animals; Toll-like receptors, Interleukin-1 receptor (IL-1R), cytosolic adaptor proteins (such as MyD88 adaptor protein) and insect and nematode Toll. Each of these groups is involved mainly in host defence, in some species also in embryogenesis[2].
TIR domain
[edit]TIR domain is about 200 amino acids long and consists of 3 conserved boxes. Between these boxes there are regions of variable lenght. If all three boxes are mutated, there is no surface expression of the protein. If only boxes one and two are mutated, there is loss of signalling activity[2]. There are also highly conserved regions between the three boxes as well. When the receptor is activated TIR domain recrutes downstream cytoplasmic signalization adaptor proteins (such as Myd88 adaptor protein) [3].
Immunoglobulin-like domain
[edit]Ig-like domain is the part of receptor which is located extracellulary. There are minimal homologies in amino acid sequences of Ig-like domains between proteins of IL-1R family but they all show characteristic Ig-fold and two β-sheets joined together by disulfide bonds which form between cystein residues. There are differences in number of Ig-like domains between members of IL-1R family [2].
IL-1R Signalization
[edit]After ligand binding, the first step of IL-1R family signalling is oligomerization of TIR domains present on receptors (IL-1R, TLR), coreceptors (IL-1R accessory protein, CD14) and adaptor molecules (MyD88). TIR domain present on receptor creates a heterodimer with TIR domain on accessory protein. This high affinity receptor complex recruites downstream signalling molecules. The signal is transduced by cytoplasmatic kinases (such as IRAKs) and by other adaptors, such as tumor necrosis factor 6 (TRAF6). The final step of signalization is phosphorilation of the inhibitory molecule IkB by IkB kinase complex leading to transcription factor NF-κB releasing. NF-κB is translocated into nucleus and by binding DNA intermediates inflammatory, alergic and non-alergic immune response [4].
Interleukin-1 receptor
[edit]The term interleukin-1 includes IL-1α, IL-1β and Interleukin 1 receptor antagonist (IL-1Ra). IL-1Rs are involved in immune host defence and hematopoiesis. IL-1R signalization activates immune response by activation of transcription of IL-1 target genes such as IL-6, IL-8, MCP-1, COX-2, IκBα, IL-1α, IL-1β, MKP-1. Components of signalization pathway of IL-1R which are involved in cellular response to IL-1 also mediate responses to other cytokines (IL-18 and IL-33), Toll-like receptors (TLRs), and many forms of cytotoxic stress. IL-1R functions as a bridge between adaptive and innate immunity.
Type I IL-1R (IL-1RI) also known as CD121a is receptor for IL-1α, IL-1β and IL-1RA. IL-1RI signalling is involved in thymocyte proliferation, B cells development, IL-2 and IL-6 production, stress responces, inflammatory responces, sleep regulation and appetite[2]. IL-1RI signaling plays also important role in Th17 development[5]. Studies of human autoimmune diseases such as sclerosis multiplex, Rheumatoid arthritis, psoriasis or autoimmune inflammatory bowel diseases show that defect in IL-1R1 signalling is responsible for Th17-mediated autoimmune diseases [6].IL-1R signalling is regulated by negative regulators such as inhibitory IL-R1 type II (IL-1RII), soluble IL-1RI and sIL-RII and IL-1Ra [7]. It can be also regulated on the level of downstream signalling molecules by inhibiting recruitment of IRAKs, or by supression of MyD88 secretion. IL-1R cooperates with receptor accessory protein and both are expressed on T cells, fibroblasts and endothelial cells [7].
IL-1RII is predominantly expressed on lymphoid and myeloid cells including monocytes, neutrophils, bone marrow cells, macrophages and B cells [8], also on T cells and epithelial cells. There are three Ig-like domains located extracellulary and highly homological with IL-1RI. Intracellulary there are 24 amino acid long domains which lack the TIR domain thus it is unable to signal [9]. IL-1RII is a surface receptor able to bind IL-1α, IL-1β and IL-1RI. It also forms a soluble form sIL-1RII. It is a decoy receptor – it inhibites activity of its ligands. Expression of IL-1RII is regulated by two different distal 5'UTRs and their associated promoter regions [9].
IL-1 receptor accessory protein
[edit]IL-1RAcP is a second receptor subunit of IL-1RI. By forming a receptor heterodimer with IL-1RI faciliates signalization due to oligomerization of TIR domains of these proteins [10]. IL-1RAcP does not bind IL-1 but it binds IL-1RI through it's Ig-like domains 1 and 2 and is necessary for IL-1R1 signalling. In response to stress or acute phase induction, a soluble form of this protein is produced by alternative splicing [11].
IL-1 receptor related protein 2
[edit]IL 1 receptor-related protein 2 (IL-1R-rp2) consists of three Ig-like extracellular domains, transmembrane domain and cytoplasmic TIR domain. It was detected in lung, epithilium, brain vaskular cells and in monocytes, keratinocytes, fibroblasts and endothelial cells. It activates NF-κB by binding IL-1ϵ [12].
- ^ Bowie A, O'Neill LA (Apr 2000). "The interleukin-1 receptor/Toll-like receptor superfamily: signal generators for pro-inflammatory interleukins and microbial products". Journal of Leukocyte Biology. 67 (4): 508–14. doi:10.1002/jlb.67.4.508. PMID 10770283.
{{cite journal}}: CS1 maint: date and year (link) - ^ a b c d Diana Boraschi, Aldo Tagliabue (2006). "The interleukin-1 receptor family". Vitamins and Hormones. 74 (4): 229–254. doi:10.1016/S0083-6729(06)74009-2. ISBN 9780127098746. PMID 17027517.
- ^ Bowie A, O'Neill LA (May 2007). "The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling". Journal Nature Reviews Immunology. 7 (4): 353–364. doi:10.1038/nri2079. PMID 17457343.
{{cite journal}}: CS1 maint: date and year (link) - ^ Michael U. Martina,*, Holger Wescheb (Sep 2002). "Summary and comparison of the signaling mechanisms of the Toll/interleukin-1 receptor family". Journal Nature Reviews Immunology: 265–280.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ Weber A, Wasiliew P, Kracht M. (Jan 2010). "Interleukin-1 (IL-1) pathway". Journal Nature Reviews Immunology.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link) - ^ Dinarello CA. (Apr 2009). "Immunological and inflammatory functions of the interleukin-1 family". Journal IMMUNOLOGY. 27: 519–550. doi:10.1146/annurev.immunol.021908.132612. PMID 19302047.
{{cite journal}}: CS1 maint: date and year (link) - ^ a b Sims et al. 1988 (Jul 1988). "cDNA expression cloning of the IL-1 receptor, a member of the immunoglobulin superfamily". Science. 241 (4865): 585–589. doi:10.1126/science.2969618. PMID 2969618.
{{cite journal}}: CS1 maint: date and year (link) CS1 maint: numeric names: authors list (link) - ^ McMahan; et al. (Oct 1991). "A novel IL-1 receptor, cloned from B cells by mammalian expression, is expressed in many cell types". The EMBO Journal. 10 (10): 2821–2832. doi:10.1002/j.1460-2075.1991.tb07831.x. PMC 452992. PMID 1833184.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: date and year (link) - ^ a b Colotta; et al. (Jul 1993). "Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4". Science. 261 (5120): 472–475. doi:10.1126/science.8332913. PMID 8332913.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: date and year (link) Cite error: The named reference "pmid2989706" was defined multiple times with different content (see the help page). - ^ O’Neill (Dec 2008). "The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress". Immunological Reviews. 226: 10–18. doi:10.1111/j.1600-065X.2008.00701.x. PMID 19161412.
{{cite journal}}: CS1 maint: date and year (link) - ^ Jensen; et al. (May 2000). "IL-1 Signaling Cascade in Liver Cells and the Involvement of a Soluble Form of the IL-1 Receptor Accessory Protein". Immunological Reviews.
{{cite journal}}: Explicit use of et al. in:|author=(help)CS1 maint: date and year (link) - ^ Lang; et al. (Dec 1998). "The type II IL-1 receptor interacts with the IL-1 receptor accessory protein: A novel mechanism of regulation of IL-1 responsiveness". Journal of Immunology. 161 (12): 6871–6877. doi:10.4049/jimmunol.161.12.6871.
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