Regulatory interactions between iron and nitric oxide metabolism for immune defense against Plasmodium falciparum infection

Iron chelation therapy of Plasmodium falciparum infection alleviates the cl inical course of cerebral malaria in children. This study assessed the unde rlying mechanisms of this therapy. Cytokine stimulation of human (intestina l cell line DLD-1) or murine cells (murine macrophage cell line RAW 264.7) resulted in increased nitric oxide (NO) formation and decreased survival of plasmodia within cocultured human erythrocytes. The addition of desferriox amine (DFO) before cytokine treatment increased both NO formation and paras ite killing but had no effect in the presence of the inhibitor of NO format ion, L-N6-(1-iminoethyl)-lysine. Moreover, peroxynitrite, which is formed a fter chemical reaction of NO with superoxide, appears to be the principal e ffector molecule for macrophage-mediated cytotoxicity toward P. falciparum, and interferon-gamma is a major regulatory cytokine for this process. The effect of DFO on the clearance of plasmodia appears to be due to enhanced g eneration of NO, rather than to limitation of iron availability to the para site.