Cytokine‐Induced Synthesis of Nitrogen Oxides in Macrophages: A Protective Host Response to Leishmania and Other Intracellular Pathogens

Fixed macrophages within tissues and the mononuclear phagocytes cabled to sites of inflammation are premier scavenger cells able to eliminate most infectious threats by a wide array of toxic effector molecules and hydrolytic enzymes. Paradoxically, a variety of protozoa, bacteria, fungi, and viruses preferentially infect and replicate within these same scavenger cells. Sites of replication include not only the phagobysosome, but also the cytoplasm of infected cells. In many instances, these microorganisms can also be killed by the infected macrophage host cell. Complex signals generated through the cytokine network of local and systemic immune reactions induce a state of activation in the infected cell which kills the intracellular parasite (presumably without killing the infected macrophage). Effector molecules that such activated macrophages use to kill and eliminate these pathogens have always been a mystery. In this review, we examine the experimental approaches that identified nitrogen oxides derived from L-arginine as essential components in the microbicidab activity of cytokineactivated macrophages, and discuss the fascinating, but complex interactions of host cells, cytokines, and infectious pathogens that regulate production and action of toxic nitrogen oxides. Details of the biochemical pathways for nitrogen oxidation of L-arginine and its regulation within mammabian cells are now emerging [1-3]. Although not fully characterized, it is known that nitric oxide (NO) is a short-lived intermediate product of this novel pathway