Definition
IL-1R antagonist (IL-1Ra) is a naturally occurring cytokine that competitively inhibits binding of IL-1 and IL-1ß to IL-1Rs without exhibiting detectable agonist activity.
Discovery
The molecule now known as IL- 1ra was first reported in 1985 as an IL- I inhibitory bioactivity of22-25 kD in the supernatants of human monocytes cultured on adherent IgG1. Dayer and colleagues independently reported studies on an IL- inhibitor of similar size in the urine of patients with fever or myelomonocytic leukemia, established that the 22-kD inhibitor semipurified from urine specifically blocked binding of 125I-IL-la to IL-I receptors on the murine thymoma cell line EL4-62.
Structural Characteristics
IL-1Ra exists as two well-characterized forms. Secretory IL-1Ra (sIL-1Ra) and intracellular IL-1Ra (icIL-1Ra) are distinct peptide products of the same IL-1Ra gene, resulting from different first exons and alternative RNA splicing. Thus, sIL-1Ra and icIL-1Ra have different mRNAs with unique transcriptional regulatory regions. sIL-1Ra is translated with a leader sequence, promptly processed to a 17-kDa peptide, glycosylated, and secreted by cells as a 22- to 25-kDa species3. The sIL-1Ra is produced by monocytes, macrophages, neutrophils, fibroblasts, and hepatocytes. The icIL-1Ra is an 18-kDa peptide that lacks a leader sequence, is not glycosylated, and remains within the intracellular space in all systems studied to date.
A third, 16-kDa IL-1Ra isoform has been observed by Western blot analysis within a variety of human cells, including keratinocytes, corneal epithelial and stromal cells,143-amino acid intracellular protein derived by alternative translation initiation from either sIL-1Ra mRNA or icIL-1Ra mRNA4.
Mode of action
IL- I ra appears to be a pure receptor antagonist, binding to IL-I receptors but not activating target cells. Human IL- I ra binds to the type I IL-I receptor on murine EL4-6.1 cells with an affinity of 150 pM, equal to the binding of human IL-la and IL- 1b(25). Furthermore, IL-Ira does not induce receptor interiorization after binding to EL4-6. 1 cells and fails to activate the protein kinase responsible for down-modulation of the epidermal growth factor receptor5.
Functions
Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro - Clinical and experimental evidence suggests that shock, arthritis, osteoporosis, colitis, leukemia, diabetes, wasting and atherosclerosis are mediated, in part, by interleukin 1 (IL-1). Inhibition of this cytokine has been a strategy for studying disease and for new drug development. A naturally-occurring IL-1 inhibitor (IL-1 receptor antagonist, IL-1ra) that blocks binding of IL-1 to its receptors has been cloned and produced in recombinant organisms. IL-1ra reduces the severity of sepsis, colitis, arthritis and diabetes in animals and is presently being tested in humans with arthritis, shock and myelogenous leukemia6.
IL-1 Receptor Antagonist: Role in Biology - Studies in transgenic and knockout mice indicate that IL-1Ra is important in host defense against endotoxin-induced injury. IL-1Ra is produced by hepatic cells with the characteristics of an acute phase protein. Endogenous IL-1Ra is produced in numerous experimental animal models of disease as well as in human autoimmune and chronic inflammatory diseases. The use of neutralizing anti-IL-1Ra antibodies has demonstrated that endogenous IL-1Ra is an important natural antiinflammatory protein in arthritis, colitis, and granulomatous pulmonary disease. Treatment of human diseases with recombinant human IL-1Ra showed an absence of benefit in sepsis syndrome. However, patients with rheumatoid arthritis treated with IL-1Ra for six months exhibited improvements in clinical parameters and in radiographic evidence of joint damage7.
The roles of IL-1 receptor antagonist in skin wound healing- A study showed that healing processes in mice deficient in IL-1 receptor antagonist (IL-1ra), was delayed along with attenuated collagen accumulation in IL-1ra knockout (KO) mice, compared with wild-type (WT) mice. On the contrary, leukocyte recruitment was exaggerated with augmented IL-1 expression in IL-1ra KO mice, implying that IL-1ra deficiency enhanced local inflammatory reaction at the wound sites. Consistently, nuclear translocation of a pro-inflammatory transcription factor, NF-?B, was significantly enhanced and prolonged in fibroblasts in IL-1ra KO mice, compared with WT mice. Previous in vitro observations demonstrated that NF-?B activation could attenuate transforming growth factor (TGF)-ß/Smad signaling pathway, which has crucial roles for collagen deposition in wound healing processes. Indeed, in IL-1ra KO mice; the TGF-ß/Smad signaling pathway was suppressed as evidenced by decreases in phosphorylated Smad2/3 and a reciprocal increase in Smad7 at the wound sites, compared with WT mice. This implied that the absence of IL-1ra resulted in aberrant NF-?B activation and reciprocal diminution in TGF-ß/Smad signaling and eventually attenuated collagen deposition during skin wound healing in vivo8.
References
1.Arend WP, FG Joslin and RJ Massoni (1985). Effects of immune complexes on production by human monocytes of interleukin 1 oran interleukin 1 inhibitor. J. Immunol., 134, 3868-3875.
2.Balavoine JF, B Rochemonteix, K Williamson, P Seckinger, A Cruchaud, and JM. Dayer (1986). Prostaglandin E2 and collagenase production by fibroblasts and synovial cells is regulated by urine-derived human interleukin 1 and inhibitor(s). J. Clin. Invest., 78, 1120-1124.
3.Haskill S, Martin G, Van Le L, Morris J, Peace A, Bigler CF, Jaffe GF, Hammerberg C, Sporn SA, Fong S, Arend WP, Ralph P (1991). cDNA cloning of an intracellular form of the human interleukin-1 receptor antagonist associated with epithelium. Proc. Natl. Acad. Sci., 88, 3681.
4.Malyak M, Guthridge JM,, Hance KR, Dower SK, Freedand JH, Arend WP (1998). Characterization of a Low Molecular Weight Isoform of IL-1 Receptor Antagonist. J Immunol.,, 161, 1997-2003.
5.Dripps DJ, Brandhuber BJ, Thompson RC, and Eisenberg SP (1991). Interleukin-l (IL-1) receptor antagonist binds to the 80-kDa IL-I receptor but does not initiate IL-I signal transduction. J. Biol. Chem., 266, 10331-10336.
6.Dinarello CA, Thompson RC (1991). Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol. Today, 12(11), 404-10.
7.Arend WP, Malyak M, Guthridge CJ and Gabay C (1998). INTERLEUKIN-1 RECEPTOR ANTAGONIST: Role in Biology. Annual Review of Immunology, 16, 27-55.
8.Ishida Y, Mukaida N and Kondo K (2008). The roles of IL-1 receptor antagonist in skin wound healing. Inflammation and Regeneration, 28, 31-35.
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