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-Inducible Nitric Oxide Output in Macrophages Is Regulated by iNOS mRNA Stability1
* 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; and
Research Institute of the McGill University Health Centre, Centre for the Study of Host Resistance, Departments of Medicine, Microbiology, and Immunology, McGill University, Montreal, Quebec, Canada
Although the effects of activated macrophages (M
) on the intracellular parasite Trypanosoma cruzi are well documented, little is known about how host-M 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 M NO generation following IFN-
stimulation, and identifying mechanisms regulating this modulation. Results show that parasite infection potentiates M to produce inducible NO synthase (iNOS) mRNA and protein as well as NO following IFN- stimulation above IFN- alone controls. This potentiation occurs through the concomitant activation of NF-
B, ERK1/ERK2 MAPK, and stress-activated protein kinase signaling pathways. Activation of the JAK/STAT pathway by IFN- then leads to STAT1
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-B 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 M 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Canadian Institutes of Health Research (to M.O.). M.O. is a member of the Canadian Institutes of Health Research Group in Host-Pathogen Interactions. M.O. is the recipient of a Canadian Institutes of Health Research Investigator Award and is a Burroughs Wellcome Fund Awardee in Molecular Parasitology. M.B. is the recipient of a Laval University/Canadian Institutes of Health Research Doctoral Award.
2 Address correspondence and reprint requests to Dr. Martin Olivier, Research Institute of the McGill University Health Centre, Centre for the Study of Host Resistance, Departments of Medicine, Microbiology, and Immunology, McGill University, Montreal, Quebec, Canada H3A 2B4. E-mail address: martin.olivier{at}mcgill.ca
3 Abbreviations used in this paper: M, macrophage; iNOS, inducible NO synthase; SAPK, stress-activated protein kinase; CAPE, caffeic acid phenethyl ester; MBMDM, murine bone marrow-derived M; ARE, AU-rich element.
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  M. Dhiman, E. S. Nakayasu, Y. H. Madaiah, B. K. Reynolds, J.-j. Wen, I. C. Almeida, and N. J. Garg Enhanced Nitrosative Stress during Trypanosoma cruzi Infection Causes Nitrotyrosine Modification of Host Proteins: Implications in Chagas' Disease Am. J. Pathol., September 1, 2008; 173(3): 728 - 740. [Abstract] [Full Text] [PDF]
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