The pathophysiologic role of indoleamine 2, 3-dioxygenase in viral infectious diseases

2011 Fiscal Year Final Research Report

• Project/Area Number: 20390167
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Kyoto University
• Principal Investigator: SAITOU Kuniaki 京都大学, 医学研究科, 教授 (80262765)
• Co-Investigator(Kenkyū-buntansha): YAMAMOTO Yasuko 京都大学, 医学研究科, 助教 (00331869) ; FUNATO Tadao 東北福祉大学, 健康科学部, 教授 (70165455)
• Co-Investigator(Renkei-kenkyūsha): ITO Hiroyasu 岐阜大学, 医学研究科, 講師 (80373075) ; SEISHIMA Mitsuru 岐阜大学, 医学研究科, 教授 (10171315)
• Project Period (FY): 2008 – 2011
• Keywords: 臨床検査医学 / 生理活性物質 / サイトカイン / 炎症・免疫

Research Abstract

The role of indoleamine 2, 3-dioxygenase(IDO) in the L-tryptophan(Trp)-kynurenine(Kyn) pathway after viral infection was investigated. 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. After viral infection(i. e myocarditis virus), the levels of Kyn increased, while those of Trp decreased, and IDO activity increased in the tissues. 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 interferons in 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. Our findings show that Kyn metabolites regulate the production of type I IFNs by decreasing the number macrophages. Consequently, modulation of the Trp-Kyn pathway may be an effective strategy for treating certain viral infectious diseases.

Research Products

• [Journal Article] L-tryptophan-mediated enhancement of susceptibility to nonalcoholic fatty liver disease is dependent on the mammalian target of rapamycin (2011)
  • Author(s): Osawa Y, Kanamori H, Seki E, Hoshi M, Ohtaki H, Yasuda Y, Ito H, Suetsugu A, Nagaki M, Moriwaki H, Saito K, Seishima M.
  • Journal Title: J Biol Chem. Volume: 286(40) Pages: 34800-8
  • DOI: doi:10.1074/jbc.M111.235473
  • Peer Reviewed
• [Journal Article] Indoleamine 2, 3-dioxygenase in tumor tissue indicates prognosis in patients with diffuse large B-cell lymphoma treated with R-CHOP (2011)
  • Author(s): Ninomiya S, Hara T, Tsurumi H, Hoshi M, Kanemura N, Goto N, Kasahara S, Shimizu M, Ito H, Saito K, Hirose Y, Yamada T, Takahashi T, Seishima M, Takami T, Moriwaki H.
  • Journal Title: Ann Hematol. Volume: 90(4) Pages: 409-16
  • DOI: DOI:10.1007/s00277-010-1093-z
  • Peer Reviewed
• [Journal Article] Ability of IDO to attenuate liver in juryin alpha-galactosylceramide-in duced hepatitis model (2010)
  • Author(s): Ito H, Hoshi M, Ohtaki H, Taguchi A, AndoK, Ishikawa T, Osawa Y, Hara A, Moriwaki H, Saito K, Seishima M.
  • Journal Title: J Immunol. Volume: 185(8) Pages: 4554-60
  • DOI: doi:10.4049/jimmunol.0904173
  • Peer Reviewed
• [Journal Article] The absence of IDO upregulates type I IFN production, resulting in suppression of viral replication in the retrovirus-infected mouse (2010)
  • Author(s): Hoshi M, Saito K, Hara A, Taguchi A, OhtakiH, Tanaka R, Fujigaki H, Osawa Y, TakemuraM, Matsunami H, Ito H, Seishima M.
  • Journal Title: J Immunol. Volume: 185(6) Pages: 3305-12
  • DOI: doi:10.4049/jimmunol.0901150
  • Peer Reviewed
• [Journal Article] Serum concentration of L-kynureninepredicts the clinical outcome of patientswith diffuse large B-cell lymphoma treated with R-CHOP (2010)
  • Author(s): Yoshikawa T, Hara T, Tsurumi H, Goto N, Hoshi M, Kitagawa J, Kanemura N, Kasahara S, Ito H, Takemura M, Saito K, Seishima M, Takami T, Moriwaki H.
  • Journal Title: Eur J Haematol. Volume: 84(4) Pages: 304-309
  • DOI: DOI:10.1111/j.1600-0609.2009.01393.x
  • Peer Reviewed
• [Journal Article] Interaction between LPS-induced NO production and IDO activity in mouse peritoneal cells in the presence of activated Valpha14 NKT cells (2009)
  • Author(s): Ohtaki H, Ito H, Ando K, Ishikawa T, HoshiM, Tanaka R, Osawa Y, Yokochi T, MoriwakiH, Saito K, Seishima M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 389(2) Pages: 229-34
  • DOI: 10.1016/j.bbrc.2009.08.120
  • Peer Reviewed
• [Journal Article] Changes in serum tryptophan catabolism as an indicator of disease activity in adult T-cell leukemia/lymphoma (2009)
  • Author(s): Hoshi M, Ito H, Fujigaki H, Takemura M, Takahashi T, Tomita E, Ohyama M, Tanaka R, Ohtaki H, Saito K, Seishima M.
  • Journal Title: LeukLymphoma. Volume: 50(8) Pages: 1372-1374
  • DOI: doi:10.1080/10428190903045393
  • Peer Reviewed
• [Journal Article] Marked increases in hippocampal neuron indoleamine 2, 3-dioxygenase via IFN-gamma-independent pathway following transient global ischemia in mouse (2009)
  • Author(s): Hoshi M, Saito K, Murakami Y, Taguchi A, Fujigaki H, Tanaka R, Takemura M, Ito H, Hara A, Seishima M.
  • Journal Title: Neurosci Res. Volume: 63(3) Pages: 194-198
  • DOI: doi:10.1016/j.neures.2008.12.003
  • Peer Reviewed
• [Remarks] ホームページ
  • URL: http://www.hs.med.kyoto-u.ac.jp/saito-k/
• [Patent(Industrial Property Rights)] 免疫抵抗性疾患耐性をもった動物の育種方法 (2010)
  • Inventor(s): 斉藤邦明、市村直也
  • Industrial Property Rights Holder: 斉藤邦明、成宮明
  • Industrial Property Number: 特願、2010、158056
  • Filing Date: 20100000