The long-term objectives of this project are to determine the roles of IL- 18 and the complement system in the induction of IL-1 and TNFalpha in collagen-induced arthritis (CIA) in mice and in rheumatoid synovial cells. IL-1 and TNFalpha are important mediators of tissue damage in rheumatoid arthritis (RA) and in CIA through stimulation of production of metalloproteinases in synovial fibroblasts and chondrocytes. The mechanisms of excess production of these cytokines in RA or CIA are probably multiple and largely unknown; IL-18 and the complement system are two potential inducers of IL1 and TNFalpha. The hypothesis to be examined in these studies is that inhibition of IL-18 with the specific IL-18 binding protein (IL-18BP), and of complement with the murine inhibitor, Crry, will attenuate the onset or ameliorate the course of CIA. This question will be addressed through three specific aims: 1) to examine the effects on CIA in mice of prevention of receptor binding of IL-18 with soluble IL-18BP; 2) to examine the effects of CIA in mice of blocking both the complement system and IL-18; and 3) to examine the relationship between production of IL-18, TNFalpha, and IL- 1beta in rheumatoid synovial tissue and cells. These experiments will utilize the administration of recombinant IL-18BP, the creation of mice transgenic for either, or both, proteins, and studies on isolated rheumatoid synovium tissue and cells. These studies are relevant to RA where IL-1 and TNFalpha are key mediators leading to inflammation and tissue destruction. The complement system and IL-18 may be important inducers of IL-1 and TNFalpha. These studies are further relevant to other autoimmune and inflammatory diseases where inhibition of injurious mechanisms at the proximal levels of complement and IL-18 may be efficacious. This research project will contribute towards the broad objective of the Autoimmunity Centers of Excellence program to study the mechanisms of new interventional approaches in both animal models of disease and in human disease.
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