- Paper Report
Regulation of IL-1 by IL-1 decoy receptor
Arthritis Research & Therapy volume 3, Article number: 66876 (2001)
Interleukin (IL)-1 is produced by synovial cells and chondrocytes in osteoarthritis (OA)-affected cartilage and plays a key role in the pathogenesis of the disease by inducing and maintaining an imbalance of cartilage homeostasis and extracellular matrix synthesis. IL-1 responses are regulated by a number of proteins. The IL-1 type I receptor (IL-1RI) and receptor accessory protein (IL-1RAcp) are required for IL-1 signalling across the cytoplasmic membrane. Furthermore, IL-1 signalling is antagonised by both the IL-1R antagonist (IL-1ra), which binds the IL-1R without inducing a biological response, and the IL-1R type II (IL-1RII), which lacks a cytoplasmic domain and therefore acts as a decoy receptor, inhibiting IL-1 activity. In this study the authors have characterised the expression of these IL-1 regulators in normal and OA cartilage and determined whether IL-1RII could inhibit IL-1 action and therefore prevent cartilage destruction.
IL-1RI and IL-1RAcp are expressed in both normal and OA-affected cartilage, while the antagonists IL-1RII and IL-1ra are not. IL-1RII was stably transfected into a human chondrocyte line. These cells expressed both surface IL-1RII and soluble IL-1RII (sIL-1RII). sIL-1RII could specifically block both IL-1?-induced nitric oxide (NO) and prostoglandin E2 production by bovine and human OA chondrocytes and IL-1?-mediated inhibition of proteoglycan synthesis. Autocrine IL-1? gene expression was also inhibited in IL-1RII transfected cells compared to nontransfected controls. sIL-1RII was more effective than sIL-1RI in neutralising the action of endogenous autocrine IL-1 in OA cartilage. IL-1-induced PGE2 expression in both human synovial and epithelial cells was also blocked by sIL-1RII.
This study demonstrates that the IL-1 decoy receptor, IL-1RII, can effectively attenuate IL-1-mediated inflammatory responses in chondrocytes, synovial cells and ex vivo cartilage, therefore identifying it as a potential therapeutic target for the treatment of OA. Inhibition of bone and cartilage damage has already been reported following treatment with the IL-1ra. Further experiments using animal models of OA will determine whether treatment with either endogenous or transgenic IL-1RII is also effective in blocking cartilage destruction in vivo.
Chondrocyte and synovial cell culture, cartilage organ culture, northern blot analysis, gene array analysis, PGE2 and nitrite assays
Attur MG, Dave M, Cipolletta C, Kang P, Goldring MB, Patel IR, Abramson SB, Amin AR: Reversal of autocrine and paracrine effects of interleukin 1 (IL-1) in human arthritis by type II IL-1 decoy receptor. Potential for pharmacological intervention. J Biol Chem. 2001, 275: 40307-40312.