REGULATION OF IL-1BETA & IL-1 INHIBITOR GENE EXPRESSION

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The long-term objective of my laboratory is to examine the possible role of monocytes and macrophages in human inflammatory diseases such as rheumatoid arthritis. The possibility exists that in inflammatory diseases where interleukin 1 (IL 1) may mediate tissue destruction, local IL 1 production by macrophages may be excessive. This unregulated IL 1 production may result primarily from the effects of differentiating or activating agents acting on tissue macrophages. The hypothesis to be examined in these proposed studies is that monocytes exposed to soluble differentiating agents, or cultured on particular substrates, will evolve into macrophages that exhibit increased levels of IL 1 production in response to triggering stimuli. These studies will examine IL 1 production in human monocytes, in vitro-derived macrophages, alveolar and synovial macrophages, and the effects of various physiologic agents or conditions that the cells might encounter in the rheumatoid joint. The proposed studies will be pursued under three specific aims: 1. To examine the mechanisms of regulation of IL-1beta production by human monocytes and in in vitro-derived macrophages in response to different triggering agents than LPS, such as PMA, silica particles, TNFalpha and a specific IL 1-inducing lymphokine. 2. To examine the mechanisms of effects on IL-1beta production by human monocytes of culture in differentiating agents such as IFN- gamma,1,25(OH)2-vitamin D3, GM-CSF or IL 4, and of culture on different substrates. 3. To examine regulation of IL-1beta production in alveolar and synovial macrophages and in cloned cell line derived from rheumatoid synovium. Monocytes and macrophages cultured in the presence of the various differentiating and triggering agents will be examined for effects on regulation of IL 1 production. The levels of regulation to be studied include transcription, translation and protein processing and secretion. These studies have direct relevance to the pathophysiology of inflammatory joint diseases such as rheumatoid arthritis where IL 1 may play an important role in the initiation of early changes in the joint as well as in mediation of tissue destruction. A greater understanding of the regulation of cytokine production may permit the development of more specific therapeutic agents in these disease.