Research on the interaction of histones in pathophysiology of sepsis and its application

• Project/Area Number: 18H02906
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 55060:Emergency medicine-related
• Research Institution: Osaka Institute of Technology
• Principal Investigator: Kawahara Ko-ichi 大阪工業大学, 工学部, 教授 (10381170)
• Co-Investigator(Kenkyū-buntansha): 丸山 征郎 鹿児島大学, 医歯学総合研究科, 特任教授 (20082282) ; 今泉 均 東京医科大学, 医学部, 教授 (70203304) ; 伊藤 隆史 鹿児島大学, 医歯学総合研究科, 特任准教授 (20381171) ; 三浦 直樹 鹿児島大学, 農水産獣医学域獣医学系, 教授 (80508036) ; 中島 利博 東京医科大学, 医学部, 教授 (90260752)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 敗血症 / DAMPs / ヒストン

Outline of Final Research Achievements

Recently, histone H3 and H4, are released into the extracellular space during sepsis and act as major mediators of death of an organism and induce platelet activation, suggesting that the extracellular histones may be damage-associated molecular patterns (DAMPs). However, histone H2A and H2B still remain unclear. In this study, the results showed that both histone H2A and H2B significantly induced the release of TNF-α in RAW264.7 cells. Histone H2A and H2B activated ERK1/2, p38MAPK and JNK, respectively. Furthermore, U0126, the inhibitor of ERK1/2 activation, significantly inhibited TNF-α induction by histone H2A and H2B in RAW264.7 cells, but not p38MAPK inhibitor SB203580 and JNK inhibitor SP600125. Therefore, our findings suggest that in the extracellular milieu, the role of Histone H2A and H2B might induce TNF-α via ERK1/2 activation in the tissue-damaged diseases such as sepsis and rheumatoid arthritis.

Academic Significance and Societal Importance of the Research Achievements

敗血症の定義が「生命を脅かす臓器障害」と改定された。これはDAMPsの重要性が示唆される。DAMPsとは臓器障害の細胞から放出され、個体死へと導く分子である。最近、ヒストンが新規DAMPsと示された。ヒストンH3、H4が細胞傷害、血小板凝集を惹起するからである。本研究成果では、ヒストンH2A、H2BがDAMPsとして証明された。すなわち、ヒストンのDAMPsとしての機能が解明された。よって、ヒストンにはそれぞれ役割があることが示唆され、新規の治療法の確立につながると確信した。

Research Products

• [Journal Article] Protective effects of recombinant human soluble thrombomodulin on ischemia reperfusion injury of spinal cord in rabbits (2021)
  • Author(s): Imagama I, Kawahara K, Ueno H, Maruyama I, Imoto H
  • Journal Title: Medical Journal of Kagoshima University Volume: 73 Pages: 16-22
  • NAID: 120007001538
  • Peer Reviewed / Open Access
• [Journal Article] Adsorptive granulocyte and monocyte apheresis: A potentially relevant therapeutic option for COVID-19 (2020)
  • Author(s): Kanekura Takuro、Kawahara Koichi
  • Journal Title: International Journal of Infectious Diseases Volume: 99 Pages: 1-2
  • DOI: 10.1016/j.ijid.2020.07.025
  • Peer Reviewed / Open Access
• [Journal Article] TLR4/MD-2 is a receptor for extracellular nucleophosmin 1 (2020)
  • Author(s): Nakatomi Kota、Ueno Hikari、Ishikawa Yuto、Salim Ronny、Mori Yuki、Kanemoto Issey、Tancharoen Salunya、Kikuchi Kiyoshi、Miura Naoki、Omori Taketo、Okuda?ashitaka Emiko、Matsumura Kiyoshi、Imaizumi Hitoshi、Motomiya Yoshihiro、Maruyama Ikuro、Kawahara Ko-Ichi
  • Journal Title: Biomedical Reports Volume: 14 Pages: 1-6
  • DOI: 10.3892/br.2020.1397
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Uric acid enhances alteplase-mediated thrombolysis as an antioxidant. (2018)
  • Author(s): Kikuchi K, Setoyama K, Tanaka E, Otsuka S, Terashi T,Nakanishi K, Takada S, Sakakima H, Ampawong S, Kawahara KI, Nagasato T, Hosokawa K, Harada Y, YamamotoM, Kamikokuryo C, Kiyama R, Morioka M, Ito T, Maruyama I, Tancharoen S.
  • Journal Title: Scientific Reports Volume: 8(1) Pages: 1-12
  • DOI: 10.1038/s41598-018-34220-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Application of a Novel Anti-Adhesive Membrane, E8002, in a Rat Laminectomy Model. (2018)
  • Author(s): Kikuchi K, Setoyama K, Terashi T, Sumizono M, Tancharoen S, Otsuka S, Takada S, Nakanishi K, Ueda K, Sakakima H, Kawahara KI, Maruyama I, Hattori G, Morioka M, Tanaka E, Uchikado H.
  • Journal Title: International Journal of Molecular Sciences Volume: 19(5) Pages: 1-9
  • DOI: 10.3390/ijms19051513
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ヒストンH2AとH2BはMD2/ERK1/2を介してTNF-αを誘導する (2020)
  • Author(s): 上野 光理, Ronny Christiadi Salim, 石濱 一貴, 朝田 成重, 山下 侑子, Tancharoen Salunya, 菊池 清志, 伊藤 隆史, 丸山 征郎, 川原 幸一
  • Organizer: 第42回日本血栓止血学会学術集会
• [Presentation] 細胞外Nucleophosminの受容体は TLR-4である (2020)
  • Author(s): 中富康太, 董建暉, 金本一誠, Ronny Christiadi Salim, 上野光理, Salunya Tancharoen, 菊池清志 伊藤隆史, 丸山征郎, 川原幸一
  • Organizer: 日本薬学会
• [Presentation] TNF-a induction by Histone H2A and H2B is mediated via ERK1/2 in RAW264.7 cells. (2019)
  • Author(s): Hikari Ueno, Kota Nakatomi, Shuto Anan, Salunya Tancharoen, Kiyoshi Kikuchi, Takashi Ito, Ikuro Maruyama, Ko-ichi Kawahara
  • Organizer: International DAMPs and Alarmins Symposium
  • Int'l Joint Research
• [Presentation] The extracellular Nucleophosmin Receptor is TLR-4 (2019)
  • Author(s): Kota Nakatomi, Ronny Christiadi Salim, Issey Kanemoto, Hikari Ueno, Dong Jianhui, Salunya Tancharoen, Kiyoshi Kikuchi, Takashi Ito, Ikuro Maruyama, Ko-ichi Kawahara.
  • Organizer: International DAMPs and Alarmins Symposium
  • Int'l Joint Research