- 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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Gretz, Elizabeth
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University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
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Banda, Nirmal K; Guthridge, Carla; Sheppard, Devon et al. (2005) Intracellular IL-1 receptor antagonist type 1 inhibits IL-1-induced cytokine production in keratinocytes through binding to the third component of the COP9 signalosome. J Immunol 174:3608-16
Ross, Aron D; Banda, Nirmal K; Muggli, Michele et al. (2004) Enhancement of collagen-induced arthritis in mice genetically deficient in extracellular superoxide dismutase. Arthritis Rheum 50:3702-11
Arend, William P; Gabay, Cem (2004) Cytokines in the rheumatic diseases. Rheum Dis Clin North Am 30:41-67, v-vi
Banda, Nirmal K; Kraus, Damian M; Muggli, Michele et al. (2003) Prevention of collagen-induced arthritis in mice transgenic for the complement inhibitor complement receptor 1-related gene/protein y. J Immunol 171:2109-15
Palmer, Gaby; Talabot-Ayer, Dominique; Szalay-Quinodoz, Ildiko et al. (2003) Mice transgenic for intracellular interleukin-1 receptor antagonist type 1 are protected from collagen-induced arthritis. Eur J Immunol 33:434-40
Banda, Nirmal K; Kraus, Damian; Vondracek, Andrea et al. (2002) Mechanisms of effects of complement inhibition in murine collagen-induced arthritis. Arthritis Rheum 46:3065-75
Arend, W P (2001) The innate immune system in rheumatoid arthritis. Arthritis Rheum 44:2224-34
Gabay, C; Marinova-Mutafchieva, L; Williams, R O et al. (2001) Increased production of intracellular interleukin-1 receptor antagonist type I in the synovium of mice with collagen-induced arthritis: a possible role in the resolution of arthritis. Arthritis Rheum 44:451-62
Arend, W P (2001) Physiology of cytokine pathways in rheumatoid arthritis. Arthritis Rheum 45:101-6
Gabay, C; Gigley, J; Sipe, J et al. (2001) Production of IL-1 receptor antagonist by hepatocytes is regulated as an acute-phase protein in vivo. Eur J Immunol 31:490-9

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