Since the molecular mechanisms of macrophage activation in response to interferon gamma (IFN-gamma) are still not well defined we have investigated whether amiloride, a specific inhibitor of the Na+/H+ antiporter, had any effect on the IFN-gamma-mediated potentiation of human monocyte and monocyte-derived macrophage capability to produce O2- (respiratory burst). Here, we demonstrate that amiloride neither inhibits the capability of IFN-gamma to activate the mononuclear phagocyte respiratory burst nor influences IFN-gamma induction of steady-state mRNA levels for 2 components of the superoxide anion-generating enzyme system. On the contrary, we show that IFN-gamma-enhanced expression of the HLA-DR alpha gene is significantly inhibited by amiloride These data indicate that Na+/H+ antiporter stimulation by IFN-gamma is not involved in the mechanism of activation of macrophage oxidative metabolism.