Cytokines and nitric oxide as effector molecules against parasitic infections

Abstract

SU M M A RYNitric oxide (NO) derived from L-arginine by the catalytic action of inducible NO synthase (iNOS) plays an important role in killing parasites. Many cell types express high levels of iNOS when activated by a number of immunological stimuli which include interferon-gamma (IFN-), tumour necrosis factor alpha, and lipopolysaccharide. IFN-is typically produced by the Th1 subset of CD4+ T cells, whose di¡erentiation depends on interleukin-12 (IL-12) produced by macrophages. Mice with a disrupted iNOS gene were highly susceptible to Leishmania major infection compared with similarly infected control wild-type mice.The mutant mice developed signi¢cantly higher levels of TH1-cell response compared with the control mice, suggesting that NO is likely to be the e¡ector molecule in the immunological control of this and other intracellular parasitic infections. To ensure their survival, the Leishmania parasites have evolved e¡ective means to inhibit NO synthesis. The highly conserved major surface glycolipids, glycoinositol-phospholipids and lipophosphoglycan (LPG), of Leishmania are potent inhibitors of NO synthesis. Furthermore, LPG can also inhibit IL-12 synthesis, thereby indirectly blocking the induction of iNOS. The evolutionary and therapeutic implications of these ¢ndings are discussed. I N T RODUC T IO NThere is considerable current interest in nitric oxide (NO) which plays an important role in a variety of biological functions (Moncada & Higgs 1993; Liew & Cox 1991;Nathan & Xie 1994;Bredt & Snyder 1994;Marletta 1994;). These include platelet aggregation, neurotransmission and cytotoxicity. NO is derived from L-arginine together with molecular oxygen in a reaction catalysed by the enzyme NO synthase (NOS), with NADPH and tetrahydrobiopterin as cofactors. NO is very unstable with a half-life between 3 and 15 s, and it is usually measured as its oxidative products, nitrite and nitrate, in culture supernatants or serum. NOS can be competitively inhibited by L-arginine analogues such as L-N G -monomethyl arginine (L-NMMA).NO is derived from the guanidino nitrogen of Larginine. L-NMMA has a methyl group at the guanidino nitrogen, therefore preventing the utilization of this nitrogen for NO synthesis. The inhibition is highly speci¢c in that the D-enantiomer, D-NMMA, is completely inert. The availability of NOS speci¢c inhibitors such as L-NMMA has contributed greatly to study in the NO ¢eld, helping it to become one of the most exciting and proli¢c areas of biomedical research.There are three isoforms of NOS, the neuronal form (nNOS), the endothelial form (eNOS), and the inducible form (iNOS). They share a number of common structural features such as NADPH-, FAD-, FMNand calmodulin-binding domains, but otherwise have little amino acid sequence homology. These are relatively large molecules, with molecular weights of 150 kDa for nNOS, and 130 for eNOS and iNOS. Furthermore, homodimerization is required for full biological activity. So far, the 3D structure of NOS is not available, nor is the precise L-arginine...

Assessment of the effect of Allium sativum on serum nitric oxide level and hepatic histopathology in experimental cystic echinococcosis in mice

“…Under different conditions, nitric oxide can have cytoprotective or cytotoxic effects depending not only on the initial insult but also on the source, rate of production, and concentration of nitric oxide in the biological milieu (Brunet et al 1999). Hence, it is the balance between nitric oxide and other inflammatory cytokines and mediators (such as TNF-a, IL-1ß, IFN-c) that is crucial in determining its effect on the host (Liew et al 1997). Several studies have suggested that nitric oxide plays a unique role in the liver, and its involvement in a variety of hepatic processes is supported by the finding that the majority of cells found in the liver, such as hepatocytes, Kupffer cells, fat-storing cells, and endothelial cells, are able to produce nitric oxide under adequate stimulation (Brunet et al 1999).…”

“…macrophages, can express high levels of iNOS when activated by immunological stimuli, e.g. interferon gamma (IFN-c) or tumour necrosis factor (TNF), thus leading to the killing of parasites (Liew et al 1997).…”

The effects of nitric oxide on the immune response during giardiasis

“…and T. cruzi). 11 It appears that evolutionary diversity has been acquired at the level of the transcription factors involved in NO synthesis in response to different kinds of stress stimuli. Three forms have been described: neuronal (nNOS, NOS1), endothelial (eNOS, NOS3) and inducible (iNOS, NOS2).…”

In vivo inhibition of inducible nitric oxide synthase by aminoguanidine influences free radicals production and macrophage activity in Trichinella spiralis infected low responders (C57BL/6) and high responders (BALB/c) mice

“…It has HELMINTHOLOGIA, 49, 4: 189 -200, 2012 In vivo inhibition of inducible nitric oxide synthase by aminoguanidine influences free radicals production and macrophage activity in Trichinella spiralis infected low responders (C57BL/6) and high responders (BALB/c) mice (Eisenstein et al, 1994;Rockett et al, 1994;Dai & Gottstein, 1999;Ren et al, 2008) and tissue pathology (Garside et al, 1992;Kolb & Kolb-Bachofen, 1992;Pacher et al, 2007). However, the role of NO in defence against T. spiralis and the other Th-2 inducing infections such as helminthoses have not been yet completely explained (James, 1995;Liew et al, 1997;Alonso-Trujillo et al, 2007;Gruden-Movsesijan & Sofronic-Milosavljevic, 2010). It is known that Th-2 immune response plays the main role during T. spiralis intestinal infection (Helmby & Grencis, 2003;Reiterová et al, 1999;Dvorožňáková et al, 2010).…”