Leishmania-induced increases in activation of macrophage SHP-1 tyrosine phosphatase are associated with impaired IFN-gamma-triggered JAK2 activation.
Leishmania-induced macrophage (Mphi) dysfunctions have been correlated with altered signaling events. Recent findings from our laboratory suggest that modulation of host protein tyrosine phosphatase (PTP) following Leishmania infection could lead to these Mphi defects. To address this issue, Mphi PTP activity and IFN-gamma-inducible signaling events were evaluated in Leishmania donovani (Ld)-infected cells. We observed that Ld promastigotes can rapidly trigger host PTP activity simultaneously with dephosphorylation of Mphi protein tyrosyl residues and inhibition of protein tyrosine kinase (PTK). Our results further revealed that Mphi SHP-1 PTP was rapidly activated by the infection. This Ld-evoked signaling alteration was reflected by absence of IFN-gamma-induced intracellular phosphorylation. IFN-gamma-inducible 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 triggered by Leishmania is partly responsible for abnormal Mphi IFN-gamma signaling and represent an important mechanism supporting persistent parasitic infection.
Blanchette
J
J
Centre de Recherche en Infectiologie Laval University Medical Research Center, Université Laval, Ste-Foy, Canada.
Racette
N
N
Faure
R
R
Siminovitch
K A
KA
Olivier
M
M
D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D007371:Interferon-gamma / Q000276:immunology* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D007893:Leishmania donovani / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D015398:Signal Transduction; D018909:src Homology Domains
D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases