The mononuclear phagocyte system is an important target for several toxicants of environmental concern. Over the past seven years we have studied the immunotoxicology of the constituent cells of this system, macrophages, and found that one important mechanism by which xenobiotics alter macrophage function is by enhancing or inhibiting macrophage activation. In parallel studies, we have begun to elucidate the signal transduction pathways involved in the response of macrophages to activating signals. Specifically we have shown that both an amiloride-- sensitive Na+/H+ exchange system (antiporter) and calcium dependent protein kinases (PKC) are directly involved in the transduction of interferon-gamma (IFNgamma) signals leading to either the priming of the cells for cytolysis or the induction of surface Ia molecules respectively. Benzoquinone (BQ) and hydroquinone (HQ), metabolites of benzene, inhibit priming of macrophages for cytolysis but have no effect on the induction of surface Ia. We thus hypothesize that BQ and HQ are blocking the transduction of the IFNgamma signal in one direction (priming/antiporter system) and not the other (Ia/PKC). We have also shown that hydrolysis of phosphoinositides leading to fluxes of Ca++, diacylglycerol generation, and the activation of PKC, and the antiporter system are also linked in a separate cascade of events to the transduction of lipopolysaccharide (LPS) signals leading to the induction of Ia, triggering of cytolysis, and the release of tumor necrosis factor (TNF). BQ also potently inhibits the triggering of cytolysis, release of TNF, and the accumulation of mRNA for TNF induced by LPS. Thus, we hypothesize that BQ blocks Ca++ and antiporter mediated events induced by LPS. By concentrating on, and examining the effects of benzene metabolites on these transduction systems we will gain insights into the molecular targets of benzene, and by the use benzene metabolites, probe deeper into the workings of signal transduction pathways involved macrophage activation.
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