The activation of mononuclear phagocytes is a fundamental host defense and homeostatic mechanism which is important to host resistance against cancer and to improved models of immunotherapy of neoplasia. Activation of mononuclear phagocytes is, moreover, important to infection with HIV-1 and the development of AIDS, atherogenesis and chronic inflammatory/destructive disorders such as rheumatoid arthritis. Over the past several years, this group of investigators has developed a well-established model of macrophage activation which is focused upon molecular mechanisms of regulation with particular emphasis upon ligand-receptor interactions, second messengers and genomic regulation. We here propose to employ this experimental model to explore in detail four selected aspects of cellular activation in molecular detail. These studies will provide useful information not only about the activation of mononuclear phagocytes but about topics of general interest to cell and molecular biology. In Project I, regulation and functional/genomic effects of activation of the sodium/hydrogen exchanger or antiport will be explored. In Project II, regulation of class II MHC genes in macrophages, arguably the single-most important antigen processing cell in the body, will be explored in terms of regulation at the genomic level. In Project III, the biologic effects of alpha-2-macroglobulin upon macrophages and suppression of class II MHC molecules will be studied. The active site in the alpha-2-macroglobulin molecule and the interrelationship between it and function too will be explored. In Project IV, the role of low molecular weight guanidine nucleotide binding proteins, resembling products of the proto-oncogene ras, in the development of mononuclear phagocytes as well as their functions such as signal transduction and secretion will be explored. The long-term goal is to establish the regulation of macrophage activation in defined molecular terms and thereby foster the rational development of drugs to manipulate mononuclear phagocytes effectively.
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