RECEPTOR-MEDIATED REGULATION OF MACROPHAGE FUNCTION

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Long-term objective of the proposed research is to elucidate the roles of Fc gamma receptors (Fc gamma R) in the regulation of functions of cells which participate in the immune response. In this proposal, efforts will be focused on the biochemical and biological properties of Fc gamma Rs present on the surface of murine macrophage surface, since many of macrophage functions, such as phagocytosis of opsonized particles, killing of tumor cells, presentation of antigens, and the secretion of factors which modulate T and B cells, have been shown to require the participation of cell surface Fc gamma Rs. Specific aims are: 1) to investigate the Fc gamma 2aR-mediated mechanism(s) of the activation of adenylate cyclase; 2) to further characterize the biochemical properties of Fc gamma 2b R protein; 3) to investigate the functional relationship between Fc gamma 2b R and the membrane adenylate cyclase system; and 4) to investigate the Fc gamma R-mediated mechanism(s) of the suppression of IFN gamma action. These aims will be approached by: 1) biochemical characterization of Fc gamma R proteins isolated from the detergent lysate of P388D1, cells; 2) production and characterization of polyclonal and monclonal antibodies directed against the isolated Fc gamma R proteins; 3) clarification of the nature of protein kinase activities associated with IgG2a-binding proteins; 4) delineation of the relationship between Fcgamma 2bR and membrane adenylate cyclase; and 5) characterization of cAMP-dependent protein kinases which may play an essential role in the modulation of the IFN gamma action. Results obtained are expected to aid our understanding of the pathways of signal transmittance, initially triggered by Fc gamma receptors at the macrophage surface. It is also expected that the proposed studies will give us informations, useful for the understanding of the biochemical sequence of events, which follows the initial signal and leads to the regulation of macrophage function.