title: Trypanosoma cruzi-mediated IFN-gamma-inducible nitric oxide output in macrophages is regulated by iNOS mRNA stability.
abstract: Although the effects of activated macrophages (Muphi) on the intracellular parasite Trypanosoma cruzi are well documented, little is known about how host-Muphi functions are affected by this pathogen before activation. This study is aimed at assessing the capacity of T. cruzi infection to modulate J77.4 murine Muphi NO generation following IFN-gamma stimulation, and identifying mechanisms regulating this modulation. Results show that parasite infection potentiates Muphi to produce inducible NO synthase (iNOS) mRNA and protein as well as NO following IFN-gamma stimulation above IFN-gamma alone controls. This potentiation occurs through the concomitant activation of NF-kappaB, ERK1/ERK2 MAPK, and stress-activated protein kinase signaling pathways. Activation of the JAK/STAT pathway by IFN-gamma then leads to STAT1alpha translocation and the transcription of a stable iNOS mRNA species. A decreased rate of iNOS mRNA degradation results in elevated levels of iNOS protein and NO production. Maximal iNOS expression is likely achieved through NF-kappaB activation by T. cruzi, whereas iNOS mRNA stability results from ERK1/ERK2 MAPK and stress-activated protein kinase activation by the infection. Taken together, our data show that T. cruzi-infected Muphi NO generation is controlled at both pre- and posttranscriptional levels and relies on signaling pathway cross-talk. This is the first report of a parasite pathogen capable of heightening host mRNA stability.
authors.affiliation: Centre de Recherche en Infectiologie, Centre Hospitalier Universitaire de Quebec, Pavillon Centre Hospitalier de l'Université Laval, and Département de Biologie Médicale, Faculté de Médecine, Université Laval, Sainte-Foy, Quebec, Canada G1V 4G2.
authors.forename: Marc
authors.initials: M
authors.lastname: Bergeron
authors.forename: Martin
authors.initials: M
authors.lastname: Olivier
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008262:Macrophage Activation; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000469:parasitology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D014349:Trypanosoma cruzi / Q000502:physiology*
chemical_list: D050832:Interferon-Stimulated Gene Factor 3; D016328:NF-kappa B; D012333:RNA, Messenger; C079868:gamma interferon activation factor; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011494:Protein Kinases