L-tryptophan-kynurenine pathway metabolites regulate type I IFNs of acute viral myocarditis in mice

Masato Hoshi, Keishi Matsumoto, Hiroyasu Ito, Hirofumi Ohtaki, Yuko Arioka, Yosuke Osawa, Yasuko Yamamoto, Hidetoshi Matsunami, Akira Hara, Mitsuru Seishima, Kuniaki Saito

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

The activity of IDO that catalyzes the degradation of tryptophan (Trp) into kynurenine (Kyn) increases after diseases caused by different infectious agents. Previously, we demonstrated that IDO has an important immunomodulatory function in immune-related diseases. However, the pathophysiological role of IDO following acute viral infection is not fully understood. To investigate the role of IDO in the L-Trp-Kyn pathway during acute viral myocarditis, mice were infected with encephalomyocarditis virus, which induces acute myocarditis. We used IDO-deficient (IDO -/-) mice and mice treated with 1-methyl-D,L-Trp (1-MT), an inhibitor of IDO, to study the importance of Trp-Kyn pathway metabolites. Postinfection with encephalomyocarditis virus infection, the serum levels of Kyn increased, whereas those of Trp decreased, and IDO activity increased in the spleen and heart. The survival rate of IDO -/- or 1-MT-treated mice was significantly greater than that of IDO +/+ mice. Indeed, the viral load was suppressed in the IDO -/- or 1-MT-treated mice. Furthermore, the levels of type I IFNs in IDO -/- mice and IDO -/- bone marrow-transplanted IDO +/+ mice were significantly higher than those in IDO +/+ mice, and treatment of IDO -/- mice with Kyn metabolites eliminated the effects of IDO -/- on the improved survival rates. These results suggest that IDO has an important role in acute viral myocarditis. Specifically, IDO increases the accumulation of Kyn pathway metabolites, which suppress type I IFNs production and enhance viral replication. We concluded that inhibition of the Trp-Kyn pathway ameliorates acute viral myocarditis.

Original languageEnglish
Pages (from-to)3980-3987
Number of pages8
JournalJournal of Immunology
Volume188
Issue number8
DOIs
Publication statusPublished - 15-04-2012
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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