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Infection and Immunity, February 2002, p. 779-786, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 70.2.779-786.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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, and Mitsuru Seishima

Department of Laboratory Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan

Received 13 April 2001/ Returned for modification 4 June 2001/ Accepted 31 October 2001

L-Tryptophan degradation by indoleamine 2,3-dioxygenase (IDO) might have an important role in gamma interferon (IFN-{gamma})-induced antimicrobial effects. In the present study, the effects of Toxoplasma gondii infection on IDO were investigated by using wild-type and IFN-{gamma}-gene-deficient (knockout) (IFN-{gamma} 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-{gamma} KO mice or in uninfected IFN-{gamma} KO mice. The levels of inducible nitric oxide synthase (iNOS) induction in infected IFN-{gamma} 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-{gamma} 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-{gamma} in the lungs, where iNOS is not induced by IFN-{gamma}. 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.

* Corresponding author. Mailing address: Department of Laboratory Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. Phone: 81-58-267-2366. Fax: 81-58-265-9027. E-mail: saito{at}cc.gifu-u.ac.jp.

Editor: J. M. Mansfield

Infection and Immunity, February 2002, p. 779-786, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 70.2.779-786.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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