TNF-α mediates the induction of nitric oxide synthase in macrophages but not in neutrophils in experimental cutaneous leishmaniasis (original) (raw)
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Inducible nitric oxide synthase and inflammation
Expert Opinion on Investigational Drugs, 1998
The quoted references are mostly recent reviews of significant relevance. eNOS, endothelial isoform of nitric oxide synthase (NOS); iNOS, inducible form of NOS; NO, nitric oxide.
Research in Immunology, 1991
In rodent cells, synthesis of nitric oxide is easily inducible by interferon-gamma in combination with a second stimulus such as tumour necrosis factor alpha or lipopolysaccharide. No comparable amount of NO synthesis could be found in human cells in vitro using various strategies in a number of different laboratories. Nevertheless, increasing evidence suggests that cytokine-inducible NO formation may also occur in humans in vivo. In murine cells, induction of NO formation is counteracted by inhibitory cytokines such as transforming growth factor [31 or macrophage-deactivating factor. Thus, one reason for the different behaviour of human cells in vitro could be a stronger expression of inhibitory cytokines under culture conditions as compared to murine cells. Other reasons for the lack of inducible NO-synthase in human cells, which remain to be investigated, may be found in differences in nitrogen metabolism in different species, e.g. interference of NO formation with arginase, methylation of arginine or different metabolism of the product NO.
European Journal of Immunology, 2003
In the Leishmania major mouse model of cutaneous leishmaniasis inducible nitric oxide synthase (iNOS) is crucial for the killing of the parasite in the skin and draining lymph node. However, the effector mechanism operating against L. major in the spleen is unknown. As reactive oxygen intermediates might play a role, we analyzed macrophages and mice lacking the gp91phox subunit of the phagocyte NADPH oxidase (phox) for their ability to combat an infection with L. major. Macrophages from wild-type and gp91phox -/mice had an equal capacity to kill L. major after activation by cytokines. Unlike iNOS, the activity of phox was dispensable for the resolution of the acute skin lesions and exerted only a limited effect on the containment of the parasites in the draining lymph node, but was essential for the clearance of L. major in the spleen. During the chronic phase of infection, parasites persisted at high levels in gp91phox -/mice, and cutaneous lesions re-emerged in approximately 60% of these mice. gp91phox deficiency did not impair the expression of iNOS or the production of TNF and IFN-+ . These results demonstrate that iNOS and phox are both required for the control of L. major in vivo and display unexpected organ-and stage-specific anti-leishmanial effects. Abbreviations: iNOS: Inducible nitric oxide synthase (NOS2) LD: Limiting dilution phox: Phagocyte NADPH oxidase ROI: Reactive oxygen intermediates SOD: Superoxide dismutase 1224 M. Blos et al.
Regulation of the Expression of Inducible Nitric Oxide Synthase
Biological Chemistry, 2000
Nitric oxide (NO), generated by the inducible isoform of nitric oxide synthase (iNOS), has been described to have beneficial microbicidal, antiviral, antiparasital, immunomodulatory, and antitumoral effects. However, aberrant iNOS induction at the wrong place or at the wrong time has detrimental consequences and seems to be involved in the pathophysiology of several human diseases. iNOS is primarily regulated at the expression level by transcriptional and post-transcriptional mechanisms. iNOS expression can be induced in many cell types with suitable agents such as bacterial lipopolysaccharides (LPS), cytokines, and other compounds. Pathways resulting in the induction of iNOS expression may vary in different cells or different species. Activation of the transcription factors NF-kappaB and STAT-1alpha, and thereby activation of the iNOS promoter, seems to be an essential step for iNOS induction in most cells. However, at least in the human system, also post-transcriptional mechanism are critically involved in the regulation of iNOS expression. The induction of iNOS can be inhibited by a wide variety of immunomodulatory compounds acting at the transcriptional levels and/or post-transcriptionally.
Cytokines and nitric oxide as effector molecules against parasitic infections
Philosophical Transactions of the Royal Society B: Biological Sciences, 1997
Nitric 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.
Blood, 1995
Nitric oxide (NO) is produced by numerous different cell types, and it is an important regulator and mediator of many processes including smooth muscle relaxation, neurotransmission, and murine macrophage- mediated cytotoxicity for microbes and tumor cells. Although murine macrophages produce NO readily after activation, human monocytes and tissue macrophages have been reported to produce only low levels of NO in vitro. The purpose of this study was to determine if stimulated human mononuclear phagocytes produce inducible nitric oxide synthase (iNOS) mRNA, protein, and enzymatic activity. By reverse transcriptase- polymerase chain reaction (RT-PCR) analysis, we show that human monocytes can be induced to express iNOS mRNA after treatment with lipopolysaccharide (LPS) and/or interferon-gamma (IFN-gamma). By immunofluorescence and immunoblot analyses, we show monocytes and peritoneal macrophages contain detectable levels of iNOS antigen after stimulations with cytokines in vitro. Cont...
Acta Veterinaria Scandinavica, 2014
Background: There are only a few studies reporting the role of nitric oxide metabolites for controlling macrophage intracellular parasitism, and these are controversial. Therefore, the present study aimed to evaluate the expression of inducible nitric oxide synthase (iNOS) in the lymph nodes and spleen of dogs affected by visceral leishmaniasis through immunohistochemistry and to determine its correlation with tissue parasite burden and serum interferon (IFN)-γ levels. Twenty-eight dogs were selected and assigned to one of two groups, symptomatic (n = 18) and asymptomatic (n = 10), according to clinical status and laboratory evaluation. A negative control group (n = 6) from a non-endemic region for visceral leishmaniasis was included as well. Results: Parasite density (amastigotes/mm 2 ) was similar between clinical groups in the lymph nodes (P = 0.2401) and spleen (P = 0.8869). The density of iNOS + cells was higher in infected dogs compared to controls (P < 0.05), without a significant difference in lymph node (P = 0.3257) and spleen (P = 0.5940) densities between symptomatic and asymptomatic dogs. A positive correlation was found between the number of iNOS + cells in lymph nodes and interferon-γ levels (r = 0.3776; P = 0.0303), and there was a negative correlation between parasites and iNOS + cell densities both in lymph nodes (r = −0.5341; P = 0.0034) and spleen (r = −0.4669; P = 0.0329). Conclusion: The negative correlation observed between tissue parasitism and the expression of iNOS may be a reflection of NO acting on the control of parasites.