Lipopolysaccharide shock reveals the immune function of indoleamine 2,3-dioxygenase 2 through regulation of IL-6/stat3 signalling

• Project/Area Number: 17H07222
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Laboratory medicine
• Research Institution: Fujita Health University
• Principal Investigator: Yamamoto Yasuko 藤田医科大学, 保健学研究科, 准教授 (00331869)
• Research Collaborator: SAITO Kuniaki 藤田医科大学, 大学院・医療科学部, 教授 (80262765)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: トリプトファン代謝 / 炎症 / 免疫調節因子 / インドールアミン酸素添加酵素2 / IDO2 / 免疫機能

Outline of Final Research Achievements

Indoleamine 2,3-dioxygenase 2 (Ido2) is a recently identified catalytic enzyme in the tryptophan-kynurenine pathway. To elucidate the biological role of Ido2 in immune function, we introduced lipopolysaccharide (LPS) endotoxin shock to Ido2 knockout mice, which led to higher mortality than that in the wild type mice. LPS-treated Ido2 KO mice had increased production of inflammatory cytokines (including interleukin-6; IL-6) in serum and signal transducer and activator of transcription 3 phosphorylation in the spleen. By contrast, the overexpression of Ido2 in the murine macrophage cell line (RAW) suppressed cytokine production and decreased stat3 expression. Finally, RAW cells overexpressing Ido2 did not alter nuclear factor kB (NF-kB) or stat1 expression, but IL-6 and stat3 expression decreased relative to the control cell line. These results reveal that Ido2 modulates IL-6/stat3 signalling and is induced by LPS, providing novel options for the treatment of immune disorders.

Academic Significance and Societal Importance of the Research Achievements

インドールアミン酸素添加酵素１（IDO1）は、炎症時における免疫抑制因子として知られている。IDO1のアイソフォームとして同定されたIDO2は、その生理的機能については未だ不明な点が多い。本研究では、IDO2が感染時における炎症抑制因子として重要な役割を果たしている事を明らかにした。IDO2が免疫系に及ぼす機序の解明や各種炎症性疾患との関係を解析することで、トリプトファン代謝酵素が創薬のターゲット分子となるのみならず、臨床サンプルの発現検索による疾患バイオマーカーとしての意義を明らかに出来ると考えられ、今後の新しい阻害剤開発も含めさらなる臨床研究に貢献できるものと思われる。

Research Products

• [Journal Article] Alteration of specific cytokine expression patterns in patients with breast cancer. (2019)
  • Author(s): Kawaguchi K, Sakurai M, Yamamoto Y, Suzuki E, Tsuda M, Kataoka TR, Hirata M, Nishie M, Nojiri T, Kumazoe M, Saito K, Toi M.
  • Journal Title: Sci Rep. Volume: 9 Issue: 1 Pages: 2924-2924
  • DOI: 10.1038/s41598-019-39476-9
  • NAID: 120006578938
  • Peer Reviewed / Open Access
• [Journal Article] Linking phencyclidine intoxication to the tryptophan-kynurenine pathway: Therapeutic implications for schizophrenia (2019)
  • Author(s): Fujigaki Hidetsugu、Mouri Akihiro、Yamamoto Yasuko、Nabeshima Toshitaka、Saito Kuniaki
  • Journal Title: Neurochemistry International Volume: 125 Pages: 1-6
  • DOI: 10.1016/j.neuint.2019.02.001
  • Peer Reviewed
• [Journal Article] Lipopolysaccharide shock reveals the immune function of indoleamine 2,3-dioxygenase 2 through the regulation of IL-6/stat3 signalling (2018)
  • Author(s): Yamamoto Yasuko、Yamasuge Wakana、Imai Shinjiro、Kunisawa Kazuo、Hoshi Masato、Fujigaki Hidetsugu、Mouri Akihiro、Nabeshima Toshitaka、Saito Kuniaki
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 15917-15917
  • DOI: 10.1038/s41598-018-34166-4
  • Peer Reviewed / Open Access
• [Journal Article] Astroglial major histocompatibility complex class I following immune activation leads to behavioral and neuropathological changes. (2018)
  • Author(s): A Sobue, N Ito, T Nagai, W Shan, K Hada, Nakajima A, Y Murakami, A Mouri, Y Yamamoto, T Nabeshima, K Saito, K Yamada
  • Journal Title: Glia Volume: 66 Issue: 5 Pages: 1034-52
  • DOI: 10.1002/glia.23299
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between increased serum GP88 (progranulin) concentrations and prognosis in patients with malignant lymphomas. (2017)
  • Author(s): Yamamoto Y, Goto N, Takemura M, Yamasuge W, Yabe K, Takami T, Miyazaki T, Takeuchi T, Shiraki M, Shimizu M, Adachi S, Saito K, Shibata Y, Nakamura N, Hara T, Serrero G, Saito K, Tsurumi H.
  • Journal Title: Clin Chim Acta Volume: 473 Pages: 139-146
  • DOI: 10.1016/j.cca.2017.07.024
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Sake lees extract improves hepatic lipid accumulation in high fat diet-fed mice. (2017)
  • Author(s): Kubo H, Hoshi M, Matsumoto T, Irie M, Oura S, Tsutsumi H, Hata Y, Yamamoto Y, Saito K
  • Journal Title: Lipids Health Dis. Volume: 16(1) Issue: 1 Pages: 106-106
  • DOI: 10.1186/s12944-017-0501-y
  • Peer Reviewed / Open Access
• [Journal Article] Effect of water-immersion restraint stress on tryptophan catabolism through the kynurenine pathway in rat tissues. (2017)
  • Author(s): Ohta Y, Kubo H, Yashiro K, Ohashi K, Tsuzuki Y, Wada N, Yamamoto Y, Saito K.
  • Journal Title: J Physiol Sci. Volume: 67(3) Issue: 3 Pages: 361-372
  • DOI: 10.1007/s12576-016-0467-y
  • NAID: 40021176369
  • Peer Reviewed
• [Presentation] Lipopolysaccharide shock reveals the immune function of indoleamine 2, 3-dioxygenase 2 through regulation of IL-6/STAT3 signalling. (2018)
  • Author(s): 1.Yasuko Yamamoto, Wakana Yamasuge, Shinjiro Imai, Kazuo Kunisawa, Masato Hoshi, Hidetsugu Fujigaki, Akihiro Mouri, Toshitaka Nabeshima, Kuniaki Saito.
  • Organizer: 15th International Society for Tryptophan Research Conference.
  • Int'l Joint Research
• [Presentation] Development of kynurenine aminotransferase II inhibitor screening assay. (2018)
  • Author(s): 2.Kyoka Yamazaki, Hidetsugu Fujigaki, Yukihiro Yoshida, Yasuko Yamamoto, Toshitaka Nabeshima, Kuniaki Saito.
  • Organizer: 15th International Society for Tryptophan Research Conference.
  • Int'l Joint Research
• [Presentation] Kynurenine 3-monooxygenase is essential for de novo biosynthesis of NAD+. (2018)
  • Author(s): 3.Yukihiro Yoshida, Hidetsugu Fujigaki, Yasuko Yamamoto, Kyoka Yamazaki, Fumika Kimura, Hisako Kubo, Tsutomu Fukuwatari, Toshitaka Nabeshima, Kuniaki Saito.
  • Organizer: 15th International Society for Tryptophan Research Conference.
  • Int'l Joint Research
• [Presentation] Kynurenine 3-monooxygenase遺伝子R452C変異解析の基礎的検討． (2017)
  • Author(s): 藤垣英嗣、吉田幸弘、山本康子、齋藤邦明
  • Organizer: 第57回日本臨床化学会年次学術集会
• [Presentation] 酵素法を用いたキヌレニン定量法の開発． (2017)
  • Author(s): 吉田幸弘、藤垣英嗣、山本康子、齋藤邦明
  • Organizer: 第57回日本臨床化学会年次学術集会
• [Presentation] Kynurenine aminotransferase 2を用いたキヌレニン測定法の開発． (2017)
  • Author(s): 吉田幸弘、藤垣英嗣、山﨑杏佳、山本康子、齋藤邦明
  • Organizer: 第38回日本トリプトファン研究会学術集