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Inhibition of IL-1? activity using IL-1RII
Arthritis Research & Therapyvolume 4, Article number: 76204 (2002)
Interleukin-1? (IL-1?) is constitutively produced 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. In normal and OA-affected human cartilage, expression of innate antagonist regulators of IL-1 is deficient. Therefore, inhibition of IL-1? action using the IL-1? type II receptor (IL-1RII), which acts as a decoy receptor, would have therapeutic potential. Indeed, IL-1?-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production by chondrocytes, synoviocytes and epithelial cells has been shown to be significantly inhibited by soluble IL-1RII. In this study, the authors have further examined the effects of reconstituting IL-1RII deficient (IL-1RII-) cells with IL-1RII using adenoviral gene transfer.
IL-1? mRNA and protein expression is 10-fold greater in OA than normal cartilage. IL-1RII+ cells expressed significant amounts of both intracellular and secreted IL-1RII. IL-1?-induced PGE2 secretion was inhibited in IL-1RII+ chondrocytes and OA synoviocytes compared to untransfected controls. IL-1?-induced IL-6 and IL-8 production and tumour necrosis factor (TNF)-a-induced PGE2 production in IL-1RII+ A549 human epithelial cells was inhibited. Induction of IL-1? mRNA by IL-1? was also inhibited in these cells. Membrane bound IL-1RII was shown to block IL-1? activity more effectively than soluble (s)IL-1RII. OA-affected cartilage incubated with IL-1RII+ synovial cells, but separated by a buoyant chamber insert, showed reduced levels of spontaneous and IL-1?-induced PGE2 and NO production. Furthermore the IL-1?-mediated reduction in proteoglycan synthesis was reversed by paracrine sIL-1RII. Human OA-affected cartilage was used to generate IL-1RII- and IL-1RII+ chondrocytes that were then transplanted onto the autologous cartilage. OA-affected cartilage transplanted with human IL-1RII+ chondrocytes showed inhibition of spontaneous and exogenous IL-1?-induced NO, PGE2, IL-6 and IL-8 production and a reversal of IL-1?-mediated reduction in proteoglycan production; controls transplanted with IL-1RII- cells showed none of these effects.
This study is an extension of the group's earlier work that demonstrated that IL-1?-induced NO and PGE2 production by chondrocytes, synoviocytes and epithelial cells is inhibited by soluble IL-1RII (see Additional information). These publications implicate the therapeutic use of IL-1RII in the treatment of OA. The current study identifies the paracrine action of transgenic IL-1RII, which would allow transduced synovial cells to also inhibit IL-1?-mediated events in nearby cartilage. However the evaluation of transgenic IL-1RII expression in an animal model of OA now needs to be carried out.
Chondrocyte isolation, culture and transplantation, synovial cell isolation, recombinant adenovirus construction, immunostaining, RT-PCR and real-time PCR, assays for PGE2, nitrite and proteoglycan synthesis
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 (Paper%20report).
Attur MG, Dave MN, Leung MY, Cipolletta C, Meseck M, Woo SLC, Amin AR: Functional genomic analysis of type II IL-1? decoy receptor: potential for gene therapy in human arthritis and inflammation. J Immunol. 2002, 168: 2001-2010.