Mononuclear phagocytes are well documented as important participants in host defense against the development and spread of cancer. This capability is dependent upon the acquisition of tumoricidal competence in response to stimuli present in the tissue microenvironment (e.g., prototypically interferon gamma (IFN gamma) and bacteria lipopolysaccaride (LPS)). The response of macrophages to these agents includes the potentiation of protein kinase C activity, the hydrolysis of phosphatidylinositol- 4,5-bisphosphate (PIP2), the associated elevation of intracellular Ca++ and stimulation of endogenous protein kinase C-mediated protein phosphorylation, and the induction of new gene expression in both early and late time frames. On the basis of these considerations we propose the following hypothesis: That macrophage tumoricidal activation is dependent in part on the transcriptional and post-transcriptional modulation of regulatory and functional gene expression. Such changes result in part from IFN gamma and/or LPS induced changes in intracellular Ca++ and/or protein kinase C-mediated protein phosphorylation. The expression of early gene products may be causally related to late gene expression. We will test this hypothesis by performing the following specific aims: 1) To isolate and characterize cloned cDNAs encoding macrophage gene products induced during tumoricidal activation by IFN gamma and LPS. 2) To analyze the regulation of IFN gamma/LPS induced early gene expression with respect to the PIP2 hydrolysis cascade and transcriptional versus post-transcriptional mechanisms. 3) To analyze the regulation of IFN gamma/LPS induced functional gene expression and acquisition of tumoricidal competence, focusing upon the relationship with early regulatory gene expression.
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