IL1 RECEPTOR ANTAGONIST INTRACELLULAR VARIANTS

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DESCRIPTION: (Adapted from the applicant's abstract) - The overall objective of this proposed research is to study the presence of the 18 kDa intracellular isoform of IL-1Ra and its role in inflammatory arthritis. The secretory sIL-1Ra is a major product of monocytes, macrophages, and neutrophils. The 18 kDa icIL-1RaI is found in the cytoplasm of epithelial cells, fibroblasts, monocytes, and macrophages. In 1994, they found icIL-1RaII, which is present in the cytoplasm of neutrophils, hepatocytes, and macrophages. The hypothesis to be examined is that icIL-1RaI is upregulated in inflammatory arthritis and this protein exhibits strong antiinflammatory effects. Furthermore, over-expression of icIL-1RaI in synovial fibroblasts and chondrocytes will lead to more potent antiinflammatory effects in collagen-induced arthritis (CIA) in mice. Three specific aims will be addressed in these studies: 1) To determine the presence and effects of icIL-1RaI in the joints from both human rheumatoid arthritis (RA) and CIA in mice; 2) to examine the effects of icIL-1RaI in CIA through using transgenic and knockout mice; and 3) to examine the effects of icIL-1RaI on the mechanisms of cartilage destruction in the SCID mouse model of rheumatoid synovitis. These studies will study the in vivo function icIL-1RaI in synovial fibroblasts and articular chondrocytes. These studies are directly related to both RA and osteoarthritis where IL-1 has been implicated as a mediator of tissue destruction through inducing the production and release of metallo-proteinases in synovial fibroblasts and articular chondrocytes. Not only does sIL-1Ra inhibit the binding of IL-1 to cell surface receptors, but they hypothesize that the intracellular isoforms of IL-1Ra will exhibit additional antiinflammatory effect inside cells.