Nitrogen Oxide in Host Defense against Parasites

Despite its small size and transitory nature, nitric oxide (NO) is a very versatile molecule. In addition to its function as a potent vasodilator and neurotransmitter, NO is important in inflammation and immunity. Indeed, in vitro experiments demonstrated that NO production by cytokine-activated rodent cells is a primary mediator of their antimicrobial and antitumoral activity. NO results from the oxidative deimination of l-arginine to l-citrulline by NO synthase (NOS), several isoforms of which have recently been isolated. Numerous cells types produce high levels of NO as a result of the expression of the inducible NO synthase (iNOS) after stimulation with bacterial product and/or cytokines, leading to parasite elimination. iNOS activity is highly regulated by cytokines, with some of them acting to induce enzyme expression (IFN-gamma, TNF-alpha), and others acting as inhibitory cytokines (TGF-beta, IL-4, IL-10, and IL-13). While a strong correlation between antiparasitic activity and NO production by cytokine-activated cells has been readily demonstrated in vitro, the relationship between generation of NO in vivo and protection against parasitic infection has only recently been addressed. Although human cells such as hepatocytes have been shown to express iNOS, the presence of such a pathway in human monocyte/macrophages is a subject of great controversy.