Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-gamma-triggered JAK2 activation

Leishmania-induced macrophage (M Phi) dysfunctions have been correlated wit h altered signaling events. Recent findings from our laboratory suggest tha t modulation of host protein tyrosine phosphatase (PTP) following Leishmani a infection could lead to these M Phi defects. To address this issue, M Phi , PTP activity and IFN-gamma-inducible signaling events were evaluated in L eishmania donovani (Ld)-infected cells. We observed that Ld promastigotes c an rapidly trigger host PTP activity simultaneously with dephosphorylation of M Phi protein tyrosyl residues and inhibition of protein tyrosine kinase (PTK). Our results further revealed that M Phi SHP-1 PTP was rapidly activ ated by the infection. This Ld-evoked signaling alteration was reflected by absence of IFN-gamma-induced intracellular phosphorylation. IFN-gamma-indu cible JAK2 PTK phosphorylation was also markedly diminished in Ld-infected cells. We also observed that co-immunoprecipitation of JAK2 with SHP-1 was considerably higher in infected as compared to uninfected cells. Altogether , these results suggest that SHP-1-mediated JAK2 dephosphorylation triggere d by Leishmania is partly responsible for abnormal M Phi IFN-gamma signalin g and represent an important mechanism supporting persistent parasitic infe ction.