L-tryptophan-L-kynurenine pathway metabolism accelerated by Toxoplasma gondii infection is abolished in gamma interferon-gene-deficient mice: Cross-regulation between inducible nitric oxide synthase and indoleamine-2,3-dioxygenase

Suwako Fujigaki, Kuniaki Saito, Masao Takemura, Naoya Maekawa, Yasuhiro Yamada, Hisayasu Wada, Mitsuru Seishima

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Abstract

L-Tryptophan degradation by indoleamine 2,3-dioxygenase (IDO) might have an important role in gamma interferon (IFN-γ) -induced antimicrobial effects. In the present study, the effects of Toxoplasma gondii infection on IDO were investigated by using wild-type and IFN- γ-gene-deficient (knockout) (IFN-γ KO) mice. In wild-type C57BL/6J mice, enzyme activities and mRNA levels for IDO in both lungs and brain were markedly increased and lung L-tryptophan concentrations were dramatically decreased following T. gondii infection. In contrast, these metabolic changes did not occur in T. gondii-infected IFN-γ KO mice or in uninfected IFN-γ KO mice. The levels of inducible nitric oxide synthase (iNOS) induction in infected IFN-γ KO mice were high in lungs and low in brain compared to those in infected wild-type mice. The extent of increased mRNA expression of T. gondii surface antigen gene 2 (SAG2) induced in lungs and brain by T. gondii infection was significantly enhanced in IFN-γ KO mice compared to wild-type mice on day 7 postinfection. Treatment with N-nitro-L arginine methyl ester, an iNOS inhibitor, increased the levels of SAG2 mRNA in brain but not in lungs and of plasma L-kynurenine after T. gondii infection. This in vivo study provides evidence that L-tryptophan depletion caused by T. gondii is directly mediated by IFN-γ in the lungs, where iNOS is not induced by IFN-γ. This study suggests that there is an antitoxoplasma mechanism of cross-regulation between iNOS and IDO and that the expression of the main antiparasite effector mechanisms for iNOS and/or IDO may vary among tissues.

Original languageEnglish
Pages (from-to)779-786
Number of pages8
JournalInfection and Immunity
Volume70
Issue number2
DOIs
Publication statusPublished - 31-01-2002

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All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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