Inhibition of interferon-gamma signaling by Leishmania donovani.
Leishmania infection causes marked down-regulation of interferon (IFN)-gamma-induced gene activity in macrophages, but the mechanism of the blockade has not been fully defined. The IFN-gamma signal transduction pathway was analyzed in Leishmania donovani-infected phorbol-differentiated U937 human promonocytic cells. IFN-gamma stimulation induced marked phosphorylation of its own receptor (IFN-gammaR)-alpha chain. Phosphorylation of the receptor subunit was significantly inhibited after 24 h of infection with the parasite, apparently because of decreased amounts of the receptor subunit. Formation of the IFN-gammaR complex, as assessed by tyrosine phosphorylation and association of Jak2, was strongly inhibited in cells infected for 24 h. Inhibition of the IFN-gammaR complex formation correlated with inhibition of STAT1alpha binding to the IFN-gamma response region. Pretreatment with purified parasite lipophosphoglycan before IFN-gamma stimulation had no effect on tyrosine phosphorylation. Thus, inhibition of tyrosine phosphorylation of the IFN-gammaR-alpha chain and subsequent signal transduction are most likely due to the decreased amount of IFN-gammaR-alpha protein after infection.
Ray
M
M
Laboratory of Parasitic Biology and Biochemistry, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20852-1448, USA.
Gam
A A
AA
Boykins
R A
RA
Kenney
R T
RT
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D006028:Glycosphingolipids / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007893:Leishmania donovani / Q000502:physiology*; D010766:Phosphorylation; D017471:Receptors, Interferon / Q000378:metabolism; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D020298:U937 Cells; D000096743:Interferon gamma Receptor
D004268:DNA-Binding Proteins; D006028:Glycosphingolipids; D007371:Interferon-gamma; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human; C008290:lipophosphonoglycan