title: Inhibition of increased indoleamine 2,3-dioxygenase activity attenuates Toxoplasma gondii replication in the lung during acute infection.
abstract: The regulation of local L-tryptophan concentrations by tryptophan-degrading enzyme, indoleamine 2,3-dioxygenase (IDO) induced by various stimuli such as interferon-γ (IFN-γ) is one of the key mechanisms in antimicrobial effect. Recently, IDO is also focused on an immunosuppressive mechanism shared by several different immune cell types. Here, we show that inhibition of increased IDO activity maybe involved in the antiparasitic mechanism during Toxoplasma gondii (T. gondii) infection in vivo. In this study, we investigated the role of IDO by using IDO-gene-deficient (IDO KO) mice and by administering a competitive enzyme inhibitor, 1-methyl-D,L-tryptophan (1MT), to wild-type mice following T. gondii infection. Although depletion of lung l-tryptophan did not occur in IDO KO mice after T. gondii infection, the increased mRNA expression of T. gondii surface antigen gene 2 (SAG2) and the inflammatory cytokines in the lung were drastically reduced in the IDO KO mice following infection. We also found that complete depletion of lung l-tryptophan was observed in wild-type mice after infection, but not in mice treated with 1MT. At the same time, 1MT suppressed the increased mRNA expression of SAG2. Taken together, we observed that the inflammatory damage was significantly decreased by the administration of 1MT in the lung after infection. Inhibition of the IDO activity or the elimination of IDO's substrate may be an effective therapy against microbial diseases.
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan. murakamiy@hs.med.kyoto-u.ac.jp
authors.forename: Yuki
authors.initials: Y
authors.lastname: Murakami
authors.forename: Masato
authors.initials: M
authors.lastname: Hoshi
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.forename: Masao
authors.initials: M
authors.lastname: Takemura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Arioka
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Matsunami
authors.forename: Tadao
authors.initials: T
authors.lastname: Funato
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
mesh_terms: D000208:Acute Disease; D000818:Animals; D000913:Antibodies, Protozoan / Q000097:blood; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D008018:Life Cycle Stages / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000469:parasitology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014122:Toxoplasma / Q000187:drug effects / Q000254:growth & development* / Q000276:immunology; D014123:Toxoplasmosis / Q000097:blood / Q000201:enzymology* / Q000276:immunology / Q000469:parasitology*; D014364:Tryptophan / Q000378:metabolism
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015800:Protozoan Proteins; D012333:RNA, Messenger; C067547:surface antigen P22, Toxoplasma; D014364:Tryptophan