Monocytes are the predominant leukocyte in atherosclerotic plaque and may contribute both to the development and instability of atherosclerotic lesions. Chemoattractant cytokines, or chemokines, are small, secreted proteins that activate monocytes, and recent data suggest they play a key role in the development of atherosclerotic lesions in animal models. Two important mechanisms by which chemokines induce leukocyte accumulation are chemotaxis and enhanced firm adhesion. The goal of this proposal is to define the signaling pathways by which chemokines enhance rapid integrin-dependent arrest of monocytes under physiological flow conditions, in contrast to the pathways responsible for chemotaxis. Recently, PT 3-kinase (P13-K) and its lipid products have been implicated in chemokine signaling in leukocytes. Our preliminary data demonstrate that P1 3-K is both necessary and sufficient for the conversion of monocyte rolling to firm adhesion to specific endothelial adhesion molecules. We will now extend our studies of P1 3-K to assess its role in monocyte adhesion to other substrates and define the role of downstream targets of P1 3-K, including Akt, cythohesin-1 and integrin linked kinase (ILK). Furthermore, we will test the hypothesis that distinct intracellular signaling pathways are responsible for monocyte chemotaxis and adhesion. Identification of the signaling pathways responsible for monocyte recruitment could provide further insights into eellu about1ar and molecular mechanisms involved a variety of human inflammatory diseases and potentially identify new targets for therapeutic intervention.
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