The mononuclear phagocyte system is an important element in the host's defenses against neoplasia but is not always effective, as the host is not always able to concentrate and appropriately modulate mononuclear phagocytes at sites of neoplastic cells. Murine macrophages are capable of lysing tumor cells in at least three distinct ways, and each of these is independently regulated, though regulation of each can involve interaction with two signals: interferon gamma and the lipid A moiety of endotoxin. Macrophages also respond to chemotactic stimuli such as N-formulated peptides. In both systems, signal transduction involves mobilization of intracellular Ca?++? and activation of protein kinase C. The signal transduction mechanisms involved when macrophages perceive chemotactic signals are also similar but distinct. In activation for cytolysis, phosphorylation of a unique set of proteins and synthesis of a new set of proteins, some of which appear to be phosphoproteins, are further cardinal events regulating activation. Activation can be pharmacologically mimicked and we are currently testing improved pharmacologic agents for inducing activation. Emerging evidence indicates that oncogene-derived products, such as products from the fos oncogene, may be important in activation. Murine and human neoplasms contain and release low molecular weight factors, reactive with monoclonal antibodies against the retrovirus envelop protein P15E, that inhibit the chemotaxis and accumulation of mononuclear phagocytes. We hypothesize that the complex activation path usually seen can be altered or deranged in tumor-bearing hosts, perhaps by such low molecular weight factors acting at one or more points in signal transduction. Several areas are currently emphasized and studied: (1) the definition in molecular terms of low molecular weight inhibitors. Numerous lines of evidence suggest that these are products related to and/or coded for by retroviruses, particularly retroviral envelope proteins such as P15E; (2) the regulation of chemotaxis and of activation for kill at the molecuIar level; (3) molecular cloning of regulatory proteins both within the macrophages and derived from tumors that appear to promote and suppress activation respectively; and (4) analyais of signal transduction in models of suppression of macrophage activation. We have developed an exciting model of down-regulation of activation by alpha 2 macroglobulin-protease complexes. (MB)
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