Glucocorticoids are potent immunosuppressive agents. The mechanisms by which these drugs exert their detrimental effects are complex. In contrast to our knowledge of steroid action on lymphocyte functions, very little is known about the modulation of macrophage functions by these agents. Thus, the long term objectives in this research area are to investigate direct effects of glucocorticoids and other immunopharmacological agents on macrophage functions such as phagocytosis, antigen presentation and tumoricidal capacity. The research proposed in this application is limited in scope to testing the following hypothesis to explain the inhibition of phagocytosis of Saccharomyces cerevisiae in dexamethasone treated cultures of murine resident peritoneal macrophages. The MECHANISM underlying the suppression of yeast ingestion in glucocorticoid treated macrophage cultures is characterized as follows: (1) It is mediated by """"""""PIP"""""""", a steroid induced Phagocytosis Inhibitory Protein, which is indistinguishable from lipocortin, a steroid induced phospholipase regulatory protein; (2) It requires active macromolecular metabolism for PIP activity to suppress yeast ingestion; (3) It is activated by achieving and maintaining effective PIP concentrations; (4) It is regulated by effector molecules that modulate phospholipase and protein kinase activities either directly or indirectly; (5) It is common to the mechanisms underlying steroid induced suppression of endocytosis in other model systems; and lastly, (6) It does not interfere with the microbicidal capacity of phagocytes exposed to these steroids. Therefore, the specific aims include (1) isolating and characterizing PIP biochemically for comparison to lipocortin, (2) investigating whether PIP expression requires de novo RNA and protein biosynthesis, (3) correlating PIP concentrations to the magnitude of the inhibitory response, (4) exploring whether PIP activity is blocked or reversed by substances that stimulate lipid enzymes, (5) determining whether PIP Is induced and acts in other endocytosis systems, and (6) ascertaining whether PIP activity is microbicidal. Achieving these specific aims will provide fresh insights into the mechanism by which steroid induced PIP suppresses the very important macrophage function of phagocytosis. This new knowledge may be applied in future studies designed to separate the beneficial anti-inflammatory effects of glucocorticoids from their detrimental immunosuppressive effects by new or novel combined chemotherapeutic-immunotherapeutic regimens.
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