Cytokine induced synthesis of nitric oxide from L-arginine: a cytotoxic mechanism that targets intracellular iron

Abstract

A cytokine inducible high output nitric oxide synthase was recently identified. It is induced by cytokines in macrophages as well as in nonmacrophage cell types. It is a product of the cell-mediated immune response and probably has multiple functional roles. Current experimental results suggest that cytokine induced synthesis of nitric oxide from L-arginine has a role in the defense of the intracellular environment against intracellular microbes. Nitrosylation of intracellular iron, particularly nonheme iron, appears to be a major biochemical fate of nitric oxide synthesized by the cytokine inducible nitric oxide synthase. This results in inhibition of redox enzymes that have nonheme iron essential for catalytic activity. Because nitric oxide is paramagnetic (has an unpaired electron) it can readily react with dioxygen and the superoxide anion to yield toxic products. As a result, the balance between beneficial and deleterious redox reactions involving nitric oxide must be tightly regulated by currently unidentified mechanisms.