Inhibition of interferon-gamma signaling by Leishmania donovani

J Infect Dis. 2000 Mar;181(3):1121-8. doi: 10.1086/315330.

Abstract

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.

MeSH terms

  • Animals
  • DNA-Binding Proteins / metabolism
  • Glycosphingolipids / pharmacology
  • Humans
  • Interferon gamma Receptor
  • Interferon-gamma / pharmacology*
  • Leishmania donovani / physiology*
  • Phosphorylation
  • Receptors, Interferon / metabolism
  • STAT1 Transcription Factor
  • Signal Transduction*
  • Trans-Activators / metabolism
  • Tyrosine / metabolism
  • U937 Cells

Substances

  • DNA-Binding Proteins
  • Glycosphingolipids
  • Receptors, Interferon
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Trans-Activators
  • lipophosphonoglycan
  • Tyrosine
  • Interferon-gamma