Role of Host Protein Tyrosine Phosphatase SHP-1 inLeishmania donovani-Induced Inhibition of Nitric Oxide Production

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Abstract
In order to survive within the macrophages of its host organism, the protozoan parasiteLeishmaniainhibits a number of critical, gamma interferon (IFN-γ)-inducible, macrophage functions, including the generation of nitric oxide. We have previously shown that the protein tyrosine phosphatase SHP-1 (Src-homology 2 domain containing phosphatase-1) is activated duringLeishmaniainfection and plays an important role in both the survival ofLeishmaniawithin cultured macrophages and disease progression in vivo by inhibiting nitric oxide production. Here we use a SHP-1−/−macrophage cell line derived frommotheatenmice to address the mechanisms by which SHP-1 prevents IFN-γ-dependent nitric oxide production duringLeishmania donovaniinfection. We show thatLeishmaniainhibits nitric oxide production in response to IFN-γ poorly in SHP-1-deficient macrophages. This correlates with the inability ofLeishmaniato alter JAK2 and mitogen-activated protein kinase extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation and to prevent nuclear translocation of transcription factors NF-κB and AP-1, although the latter two to a lesser extent. Surprisingly,Leishmaniainactivated the transcription factor STAT1 to a similar extent in SHP-1-deficient and wild-type macrophages, so STAT1 is not necessary for nitric oxide production by infected macrophages. Overall, this study demonstrates that induction of SHP-1 byLeishmaniais vital for inhibition of nitric oxide generation and that this inhibition occurs through the inactivation of JAK2 and ERK1/2, and transcription factors NF-κB and AP-1.