Leishmania inhibits STAT1-mediated IFN-γ signaling in macrophages: increased tyrosine phosphorylation of dominant negative STAT1β by Leishmania mexicana

Previous studies have demonstrated that Leishmania donovani attenuates STAT1-mediated signaling in macrophages; however it is not clear whether other species of Leishmania, which cause cutaneous disease, also interfere with macrophage IFN-γ signaling. Therefore, we determined the effect of Leishmania major and Leishmania mexicana infection on STAT1-mediated IFN-γ signaling pathway in J774A.1 and RAW264.7 macrophages. We found that both L. major and L. mexicana suppressed IFNγRα (α subunit of interferon gamma receptor) and IFN-γRβ (β subunit of interferon gamma receptor) expression, reduced levels of total Jak1 and Jak2, and down-regulated IFN-γ-induced Jak1, Jak2 and STAT1 activation. The effect of L. mexicana infection on Jak1, Jak2 and STAT1 activation was more profound when compared with L. major. Although tyrosine phosphorylation of STAT1α was decreased in IFN-γ stimulated macrophages infected with L. major or L. mexicana, those infected with L. mexicana showed a significant increase in phosphorylation of the dominant negative STAT1β. These findings indicate that L. major and L. mexicana attenuate STAT1-mediated IFN-γ signaling in macrophages. Furthermore, they also demonstrate that L. mexicana preferentially enhances tyrosine phosphorylation of dominant negative STAT1β, which may be one of the several survival mechanisms used by this parasite to evade the host defense mechanisms.