RECEPTOR-MEDIATED REGULATION OF MACROPHAGE FUNCTIONS

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Our long-term objectives are to clearly delineate the biochemical pathways which are triggered by the interaction between ligand and specific cell surface receptor and lead to modulation of macrophage functions. We will focus our efforts on the biochemical and biological properties of Fc-gamma- Rs present on the surface of murine macrophage, because many of macrophage functions, such as phagocytosis of opsonized particles, killing of tumor cells, presentation of antigens, and secretion of factors which regulate T and B cells, have been shown to require the participation of cell surface Fc-gamma-Rs. Specific aims are to investigate: 1) physiological roles of casein kinase II (CKII) activity associated with Fc-gamma(2a)R; 2) properties of Fc-gamma(2a)R by biochemical and molecular biological approaches; 3) the roles of G proteins in the regulation of phospholipases C and A2 activated by immune complex or LPS; and 4) the role of cAMP-dependent protein kinase (cAK) and protein kinase C (PKC) in the regulation of macrophage functions. We will approach to these specific aims by: 1) biochemical characterization of Fc-gamma(2a)R complex; 2) cloning of the gene coding for Fc-gamma(2a)R by subtractive hybridization method; 3) characterization of Fc-gamma(2a)R-associated CKII activity; 4) investigation of Fc-gamma-R-cytoskeletal interaction during phagocytosis; 5) comparison of the nature of G proteins among macrophage cell lines; and 6) characterization of cAK and PKC. Results obtained are expected to promote our understanding of the biochemical pathways of signal transmittance, which are initially triggered by cell surface FC-gamma-R and leads to the regulation of macrophage functions.