The mechanism of interferon-gamma induced anti Toxoplasma gondii by indoleamine 2,3-dioxygenase and/or inducible nitric oxide synthase vary among tissues.
L-Tryptophan degradation by indoleamine 2,3-dioxygenase (IDO) induction and reactive nitrogen intermediates produced by inducible nitric oxide synthase (iNOS) induction are important factors for IFN-gamma-induced anti-toxoplasma activities. In the present study, the effects of acute Toxoplasma gondii (T. gondii) infection on IDO and iNOS were investigated using wild-type (WT) and IFN-gamma gene-deficient (IFN-gamma KO) mice. In the WT C57BL/6J mice, enzyme activities and mRNA levels of IDO in both lung and brain were markedly increased, and lung L-tryptophan concentrations were dramatically decreased following infection. In contrast, these metabolic changes did not occur in infected IFN-gamma KO mice. The level of iNOS induction in the infected IFN-gamma KO mice was high in lung and low in brain compared to that in infected WT mice. The extent of increased mRNA expression of T. gondii surface antigen gene 2 (SAG2) in lung and brain induced by infection was significantly enhanced in the IFN-gamma KO mice compared to that in WT mice. Treatment with N-nitro-L-arginine methyl ester, an iNOS inhibitor, increased the levels of SAG2 mRNA in brain, but not in lung following infection. This in vivo study provides evidence that L-tryptophan depletion caused by T. gondii is directly mediated by IFN-gamma in the lung, where iNOS is not induced by IFN-gamma. This study suggests that there is an anti-toxoplasma mechanism of cross-regulation between iNOS and IDO and that the expression of main anti-parasite effector mechanisms of iNOS and/or IDO may vary among tissues.
Fujigaki
Suwako
S
Department of Laboratory Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. fujigaks@intra.nimh.nih.gov
Takemura
Masao
M
Hamakawa
Hidetsugu
H
Seishima
Mitsuru
M
Saito
Kuniaki
K
D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007737:Kynurenine / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution; D014122:Toxoplasma / Q000276:immunology / Q000472:pathogenicity*; D014124:Toxoplasmosis, Animal / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D016781:Toxoplasmosis, Cerebral / Q000276:immunology / Q000378:metabolism / Q000469:parasitology; D014364:Tryptophan / Q000378:metabolism; D014366:Tryptophan Oxygenase / Q000235:genetics / Q000378:metabolism*
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D007737:Kynurenine; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse