CYTOKINES AND NITRIC-OXIDE AS EFFECTOR MOLECULES AGAINST PARASITIC INFECTIONS

Nitric oxide (NO) derived from L-arginine by the catalytic action of i nducible NO synthase (iNOS) plays an important role in killing parasit es. Many cell types express high levels of iNOS when activated by a nu mber of immunological stimuli which include interferon-gamma (IFN-gamm a), tumour necrosis factor alpha, and lipopolysaccharide. IFN-gamma is typically produced by the Th1 subset of CD4+ T cells, whose different iation depends on interleukin-12 (IL-12) produced by macrophages. Mice with a disrupted iNOS gene were highly susceptible to Leishmania majo r infection compared with similarly infected control wild-type mice. T he mutant mice developed significantly higher levels of TH1-cell respo nse compared with the control mice, suggesting that NO is likely to be the effector molecule in the immunological control of this and other intracellular parasitic infections. To ensure their survival, the Leis hmania parasites have evolved effective means to inhibit NO synthesis. The highly conserved major surface glycolipids, glycoinositol-phospho lipids and lipophosphoglycan (LPG), of leishmania are potent inhibitor s of NO synthesis. Furthermore, LPG can also inhibit IL-12 synthesis, thereby indirectly blocking the induction of iNOS. The evolutionary an d therapeutic implications of these findings are discussed.