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Published online before print December 14, 2006

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(Journal of Leukocyte Biology. 2007;81:835-844.)
© 2007 by Society for Leukocyte Biology

Role of protein tyrosine phosphatases in the regulation of interferon--induced macrophage nitric oxide generation: implication of ERK pathway and AP-1 activation

Julie Blanchette^*, Philippe Pouliot and Martin Olivier^*,,1

^* Centre de Recherche en Infectiologie and Département de Biologie Médicale, Centre Hospitalier Universitaire de Québec, Pavillon CHUL, Université Laval, Ste-Foy, Québec, Canada; and
Centre for the Study of Host Resistance, The Research Institute of the McGill University Health Centre, Departments of Experimental Medicine, Microbiology and Immunology, Faculty of Medicine, McGill University, Montréal, Québec, Canada

¹ Correspondence: McGill University, Department of Microbiology and Immunology, Duff Medical Building, Room 511, 3775 University Street, Montréal, Québec, Canada H3A 2B4. E-mail: martin.olivier{at}mcgill.ca

NO is a potent molecule involved in the cytotoxic events mediated by macrophages (MØ) against microorganisms. We reported previously that inhibition of MØ protein tyrosine phosphatases (PTPs) mediates a protective effect against Leishmania infection, which was NO-dependent. Herein, we show that the PTP inhibitors of the peroxovanadium (pV) class, bpV(phen) and bpV(pic), can similarly increase murine MØ IFN--induced NO generation. Using various second messenger (JAK2, MEK, Erk1/Erk2, and p38) antagonists, we found that the Erk1/Erk2 pathway was the principal pathway submitted to regulation by PTPs in the context of IFN--driven MØ activation and increase in NO production. We observed that bpV(phen) increases inducible NO synthase (iNOS) expression, resulting in enhanced NO production, whereas the bpV(pic) increase of NO production does not seem to result from a modulation of iNOS expression. Transcription factors STAT-1 and NF-B, recognized for their importance in NO generation, were not affected by the pV treatment. However, AP-1 was strongly activated by bpV(phen) but not by bpV(pic). Collectively, our results suggest that increased IFN--induced NO production, observed after bpV(phen) treatment, involves the activation of the transcription factor AP-1 by Erk1/Erk2- and stress-activated protein kinase/JNK-dependent transduction mechanisms.

Key Words: protein tyrosine kinases • transcription factors • peroxovanadiums • second messengers

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