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

NO is a potent molecule involved in the cytotoxic events mediated by macropbages (M circle divide) against microorganisms. We reported previously that inbiition of MO protein tyrosine phospbatases (PTPs) mediates a protective effect against Leishnmania 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 M circle divide IFN-gamma-induced NO generation. Using various second messenger (JAK2, MEK, Erkl/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-gamma-driven M circle divide 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-lot and NF-kappa B, recoppuzed 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-gamma-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.