PHOSPHOLIPASE REGULATION OF MONOCYTE CHEMOTAXIS TO MCP-1

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DESCRIPTION (provided by applicant): Monocytes are major participants in inflammatory responses and are mediators of chronic inflammation. Monocyte chemotactic factor 1 (MCP-1) is a critical chemotactic factor involved in attracting monocytes from the blood into tissues. This chemotactic cytokine has been shown to be a particularly important for the extravasation of monocytes into vessel walls in atherogenesis. Atherosclerosis-prone mice, when rendered deficient in either MCP-1 or its receptor, CCR2, develop significantly less atherosclerosis than their normal counterparts. Furthermore, MCP-1 has also been associated with a series of other chronic human inflammatory diseases including rheumatoid arthritis, viral meningitis, psoriasis, and inflammatory bowel disease. To date, we have a very cursory understanding of the signal transduction pathways regulating the chemotactic response of monocytes to MCP-I. In this application we propose experiments to elucidate the pathways regulating this central inflammatory process. Recent studies from our laboratory have identified a novel role for phospholipases A2 in regulating monocyte chemotaxis. When primary monocytes are rendered deficient in the expression of either cPLA2 or iPLA2 they fail to respond to the chemotactic stimulus of MCP-I. These pathways appear to operate independently in regulating the chemotactic response. It is clear that lipid signaling pathways are integral regulators of this monocyte chemotactic response. In this proposal we present a research plan to investigate how these PEA2 pathways regulate chemotaxis. In Aim 1 we will determine how these phospholipases relate to the few other pathways that have been identified in regulating MCP-l-induced monocyte chemotaxis and in the process we will explore the best approaches for selectively intervening in this process. We will examine the contributions of phospholipase D and AA metabolites in regulating chemotaxis and will explore the role of phospholipases in influencing cytoskeletal rearrangement and other cell processes involved in monocytic responses to MCP-1. These studies will significantly advance our understanding of this key inflammatory event.