The role of IL-17A-induced mRNA stabilization in immune-related diseases

• Project/Area Number: 17K08263
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Hokkaido University
• Principal Investigator: Muromoto Ryuta 北海道大学, 薬学研究院, 講師 (30455597)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: IL-17 / サイトカイン / シグナル伝達 / mRNA安定性制御 / 炎症 / mRNA安定化 / 免疫関連疾患

Outline of Final Research Achievements

IL-17 is an inflammatory cytokine, which is important in the pathogenesis of autoimmune diseases. In this study we aimed to elucidate the mechanism of the IL-17 action.We have identified the molecules that mediate the signal transduction process in IL-17-induced mRNA stabilization. Further, we have found that dimethyl fumarate and TBK1 inhibitor can suppress the signal transduction leading to mRNA stabilization.

Academic Significance and Societal Importance of the Research Achievements

本研究により、サイトカインIL-17がmRNA安定化反応を介して炎症を促進する際の分子機構の一端が解明された。また、IL-17によって起こるmRNA安定化反応を抑制できる低分子化合物が同定された。このような効果をもつ化合物はIL-17に惹起される炎症を伴う免疫疾患の抑制に役立てられる可能性があり、また、研究のツールとして用いることで分子機構のさらなる詳細を解明するための後続研究に利用できる。

Research Products

• [Journal Article] Dimethyl fumarate dampens IL-17-ACT1-TBK1 axis-mediated phosphorylation of Regnase-1 and suppresses IL-17-induced IκB-ζ expression (2020)
  • Author(s): Ohgakiuchi Yui、Saino Yuka、Muromoto Ryuta、Komori Yuki、Sato Ami、Hirashima Koki、Kitai Yuichi、Kashiwakura Jun-ichi、Oritani Kenji、Matsuda Tadashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 521 Issue: 4 Pages: 957-963
  • DOI: 10.1016/j.bbrc.2019.11.036
  • NAID: 120007097378
  • Peer Reviewed / Open Access
• [Journal Article] The mechanism of Tyk2 deficiency-induced immunosuppression in mice involves robust IL-10 production in macrophages (2020)
  • Author(s): Hirashima Koki、Muromoto Ryuta、Minoguchi Hiroya、Matsumoto Tomohiro、Kitai Yuichi、Kashiwakura Jun-ichi、Shimoda Kazuya、Oritani Kenji、Matsuda Tadashi
  • Journal Title: Cytokine Volume: 130 Pages: 155077-155077
  • DOI: 10.1016/j.cyto.2020.155077
  • NAID: 120007097398
  • Peer Reviewed / Open Access
• [Journal Article] IκB-ζ Expression Requires Both TYK2/STAT3 Activity and IL-17-Regulated mRNA Stabilization (2019)
  • Author(s): Muromoto Ryuta、Tawa Keisuke、Ohgakiuchi Yui、Sato Ami、Saino Yuka、Hirashima Koki、Minoguchi Hiroya、Kitai Yuichi、Kashiwakura Jun-ichi、Shimoda Kazuya、Oritani Kenji、Matsuda Tadashi
  • Journal Title: ImmunoHorizons Volume: 3 Issue: 5 Pages: 172-185
  • DOI: 10.4049/immunohorizons.1900023
  • NAID: 120007097377
  • Peer Reviewed / Open Access
• [Journal Article] STAP-2 interacts with Pyk2 and enhances Pyk2 activity in T-cells. (2017)
  • Author(s): Saitoh K, Tsuchiya T, Kashiwakura JI, Muromoto R, Kitai Y, Sekine Y, Oritani K, Matsuda T
  • Journal Title: Biochem Biophys Res Commun Volume: 488(1) Issue: 1 Pages: 81-87
  • DOI: 10.1016/j.bbrc.2017.05.010
  • NAID: 120006477491
  • Peer Reviewed / Open Access
• [Journal Article] A Novel α9 Integrin Ligand, XCL1/Lymphotactin, Is Involved in the Development of Murine Models of Autoimmune Diseases. (2017)
  • Author(s): Matsumoto N, Kon S, Nakatsuru T, Miyashita T, Inui K, Saitoh K, Kitai Y, Muromoto R, Kashiwakura JI, Uede T, Matsuda T.
  • Journal Title: J Immunol. Volume: 199 Issue: 1 Pages: 82-90
  • DOI: 10.4049/jimmunol.1601329
  • NAID: 120007007782
  • Peer Reviewed / Open Access
• [Journal Article] Biochanin A enhances RORγ activity through STAT3-mediated recruitment of NCOA1 (2017)
  • Author(s): Takahashi Miki、Muromoto Ryuta、Kojima Hiroyuki、Takeuchi Shinji、Kitai Yuichi、Kashiwakura Jun-ichi、Matsuda Tadashi
  • Journal Title: Biochem Biophys Res Commun. Volume: 489 Issue: 4 Pages: 503-508
  • DOI: 10.1016/j.bbrc.2017.05.181
  • Peer Reviewed / Open Access
• [Journal Article] STAP-2 protein promotes prostate cancer growth by enhancing epidermal growth factor receptor stabilization. (2017)
  • Author(s): Kitai Y, Iwakami M, Saitoh K, Togi S, Isayama S, Sekine Y, Muromoto R, Kashiwakura JI, Yoshimura A, Oritani K, Matsuda T
  • Journal Title: J Biol Chem Volume: 292(47) Issue: 47 Pages: 19392-19399
  • DOI: 10.1074/jbc.m117.802884
  • NAID: 120006539248
  • Peer Reviewed / Open Access
• [Presentation] Tyk2欠損マウスにおける免疫反応抑制にはマクロファージでのIL-10産生増強が関与する (2020)
  • Author(s): 室本 竜太、平島 洸基、美濃口 広弥、松田 正
  • Organizer: 日本薬学会第140年会
• [Presentation] IL-17/TBK1シグナルによるIκB-ζ mRNA安定化機構の解明 (2019)
  • Author(s): 斎野由佳、大垣内優衣、室本竜太、松田正
  • Organizer: 日本薬学会北海道支部第146回例会
• [Presentation] IL-17誘導性IκB-ζ mRNA安定化応答におけるACT1の機能解析 (2019)
  • Author(s): 小森雄喜、大垣内優衣、斎野由佳、室本竜太、松田正
  • Organizer: 日本薬学会北海道支部第146回例会
• [Presentation] STAT1 acts as a negative regulator or IκB-ζ gene transcription (2019)
  • Author(s): 室本竜太、佐藤亜美、松田正
  • Organizer: 第26回日本免疫毒性学会学術年会
• [Presentation] Opposing roles of STAT1 and STAT3 in IκB-ζ gene transcription (2019)
  • Author(s): Ami Sato, Ryuta Muromoto, Tadashi Matsuda
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] IL-17誘導性IκB-ζ mRNA安定化へのTBK1の関与 (2019)
  • Author(s): 斎野由佳、大垣内優衣、室本竜太、松田正
  • Organizer: 日本薬学会第139年会
• [Presentation] 抗炎症サイトカインIL-10産生機構におけるTyk2の関与 (2018)
  • Author(s): 美濃口広弥 平島洸基 室本竜太 松田正
  • Organizer: 日本薬学会北海道支部第145回例会
• [Presentation] 転写子コアクチベーターIκB-ζ ｍRNA安定化機構の解明 (2018)
  • Author(s): 斎野由佳 大垣内優衣 室本竜太 松田正
  • Organizer: 日本薬学会北海道支部第145回例会
• [Presentation] 角化細胞におけるIL-17誘導性IκB-ζ発現機構の解析 (2018)
  • Author(s): 室本竜太、大垣内優衣、斎野由佳、佐藤亜美、多和佳佑、松田正
  • Organizer: 第25回日本免疫毒性学会学術年会
• [Presentation] Tyk2 regulates Protein kinase A-IL-10 pathway and promotes inflammation (2018)
  • Author(s): Koki Hirashima, Ryuta Muromoto and Tadashi Matsuda
  • Organizer: 第47回日本免疫学会学術集会 The 47th Annual Meeting of The Japanese Society for immunology
• [Presentation] Constitutive post-transcriptional suppression of IκB-ζ expression mediated by Regnase-1 is counteracted by IL-17 signaling (2018)
  • Author(s): Yui Ohgakiuchi, Ryuta Muromoto, Tadashi Matsuda
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] 表皮角化細胞におけるIκB-ζ発現制御機構の解析 (2017)
  • Author(s): 大垣内優衣、多和佳佑、室本竜太、松田 正
  • Organizer: 日本薬学会北海道支部第144回例会
• [Presentation] P. acnes誘導性炎症応答とTyk2の新規機能 (2017)
  • Author(s): 平島洸基、室本竜太、松田正
  • Organizer: 第54回日本生化学会北海道支部例会
• [Presentation] 表皮角化細胞におけるIL-17誘導性IκB-ζ発現機構の解明 (2017)
  • Author(s): 大垣内優衣、多和佳佑、室本竜太、松田正
  • Organizer: 第54回日本生化学会北海道支部例会
• [Presentation] JAKファミリーキナーゼ阻害が角化細胞のIL-17応答に及ぼす影響 (2017)
  • Author(s): 室本 竜太、多和 佳佑、大垣内 優衣、松田 正
  • Organizer: 第24回日本免疫毒性学会学術年会
• [Presentation] P. acnes誘導性急性炎症におけるTyk2の新たな役割 (2017)
  • Author(s): 平島 洸基、室本 竜太、松田 正
  • Organizer: 第16回次世代を担う若手ファーマバイオフォーラム2017
• [Presentation] TYK2-mediated basal STAT3 activity and IL-17-induced mRNA stabilization coordinately dictate the expression level of IκB-ζ in keratinocytes (2017)
  • Author(s): Ryuta Muromoto, Keisuke Tawa, Yui Ohgakiuchi and Tadashi Matsuda
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society (ICIS 2017)
  • Int'l Joint Research
• [Presentation] Basal STAT3 activity maintained by TYK2 is required for IL-17-induced IκB-ζ expression in keratinocytes (2017)
  • Author(s): Ryuta Muromoto and Tadashi Matsuda
  • Organizer: 第46回日本免疫学会学術集会
• [Presentation] Tyk2 positively regulates P. acnes-induced acute inflammation (2017)
  • Author(s): Koki Hirashima, Ryuta Muromoto and Tadashi Matsuda
  • Organizer: 第46回日本免疫学会学術集会