Investigation of immune mechanism of PGD2/CRTH2 in severe infectious diseases

• Project/Area Number: 24591488
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Infectious disease medicine
• Research Institution: Keio University
• Principal Investigator: ISHII MAKOTO 慶應義塾大学, 医学部, 講師 (30317333)
• Co-Investigator(Renkei-kenkyūsha): FUJII Hideki 琉球大学, 医学研究科, 准教授 (50356250)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: CRtH2 / 敗血症 / エピジェネティクス / プロスタグランジンD2 / CRTH2 / プロシタグランジンD2 / インフルエンザウィルス

Outline of Final Research Achievements

We evaluated the role of CRTH2 using a mice model of polymicrobial sepsis. CRTH2 knockout (-/-) mice were highly resistant to sepis and peritoneal bacterilal load in CRTH2-/- mice was significantly lower as compared to that in wild-type mice.Pharmacological inhibition of Gr-1, a neutrophil marker, and CXCR2 attenuated the protective effects aganist sepsis in CRTH2-/- mice, indicating that CXCR2-expressing neutrophils play protective roles in CRTH2-/- mice in this sepsis model. Moreover, acetylation of histone H3 at CXCR2 promoter in perippheral neutrophils was reduced 2 h after the surgery in wild-type neutrophils, while that in CRTH2-/- mice was not reduced 2 h after the surgery, suggesting that CXCR2 expression is regulated by epigenetic change.

Research Products

• [Journal Article] The diagnostic usefulness of 18F-fluorodoxyglucose-positron emission tomography/CT in SAPHO syndrome (2015)
  • Author(s): Namkoong H, Ishii M, Tasaka S, Betsuyaku T
  • Journal Title: BMJ Case Rep Volume: undecided Pages: bcr2015209394-bcr2015209394
  • DOI: 10.1136/bcr-2015-209394
  • Peer Reviewed / Open Access
• [Journal Article] Fatal fulminant pneumonia caused by methicillin-sensitive Staphylococcus aureus negative for major high-virulence factors secondary to influenza B virus infection (2015)
  • Author(s): Masaki K, Ishii M, Anraku M, Namkoong H, Miyakawa R, Nakajima T, Fukunaga K, Naoki K, Tasaka S, Soejima K, Sayama K, Sugita K, Iwata S, Cui L,
  • Journal Title: Am J Case Rep Volume: 0
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of the immunogenicity and safety of polysaccharide and protein-conjugated pneumococcal vaccines among the elderly aged 80 years or older in Japan: an open-labeled randomized study. (2015)
  • Author(s): Namkoong H, Funatsu Y, Oishi K, Akeda Y, Hiraoka R, Takeshita K, Asami T, Yagi K, Kimizuka Y, Ishii M, Tasaka S, Suzuki Y, Iwata S, Betsuyaku T, Hasegawa N.
  • Journal Title: Vaccine Volume: 33 Issue: 2 Pages: 327-332
  • DOI: 10.1016/j.vaccine.2014.11.023
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary nocardiosis caused by Nocardia cyriacigeorgica in patients with Mycobacterium avium complex lung disease: two case reports. (2014)
  • Author(s): Yagi K, Ishii M, Namkoong H, Asami T, Fujiwara H, Nishimura T, Saito F, Kimizuka Y, Asakura T, Suzuki S, Kamo T, Tasaka S, Gonoi T, Kamei K, Betsuyaku T, Hasegawa N.
  • Journal Title: BMC Infect Dis. Volume: 14 Pages: 684-684
  • Peer Reviewed / Open Access
• [Journal Article] The efficacy, safety, and pharmacokinetics of biapenem administered thrice daily for the treatment of pneumonia in the elderly. (2014)
  • Author(s): Namkoong H, Kameyama Y, Yasuda H, Nakayama S, Kaneko H, Kawashima C, Terajima T, Maezawa K, Hayashi T, Sandoh M, Ishii M, Tasaka S, Kanayama A, Kobayashi I, Betsuyaku T, Kizu J, Iwata S, Sato Y, Hasegawa N
  • Journal Title: J Infect Chemother Volume: 20 Issue: 6 Pages: 356-360
  • DOI: 10.1016/j.jiac.2013.12.010
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacokinetics of arbekacin in bronchial epithelial lining fluid of healthy volunteers. (2014)
  • Author(s): Funatsu Y, Hasegawa N, Fujiwara H, Namkoong H, Asami T, Tasaka S, Kimizuka Y, Kamata H, Ishii M, Iketani O, Ogata H, Iwata S, Betsuyaku T
  • Journal Title: J Infect Chemother Volume: 20 Issue: 10 Pages: 607-611
  • DOI: 10.1016/j.jiac.2014.05.007
  • Peer Reviewed / Open Access
• [Journal Article] Modulation of murine macrophage TLR7/8-mediated cytokine expression by mesenchymal stem cell-conditioned medium (2013)
  • Author(s): 15.Asami T, Ishii M, Fujii H, Namkoong H, Tasaka S, Matsushita K, Ishii K, Yagi K, Fujiwara H, Funatsu Y, Hasegawa N, Betsuyaku T
  • Journal Title: Mediators Inflamm Volume: undecided Pages: 1-13
  • DOI: 10.1155/2013/264260
  • Peer Reviewed
• [Journal Article] A case of skeletal tuberculosis and psoas abscess: disease activity evaluated using 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (2013)
  • Author(s): Kimizuka Y, Ishii M, Murakami K, Ishioka K, Yagi K, Ishii K, Watanabe K, Soejima K, Betsuyaku T, Hasegawa N
  • Journal Title: BMC Med Imaging Volume: 13 Issue: 1 Pages: 37-37
  • DOI: 10.1186/1471-2342-13-37
  • Peer Reviewed
• [Journal Article] Roles of IL-17 in an experimental Legionella pneumonia model. (2012)
  • Author(s): Kimizuka Y, Kimura S, Saga T, Ishii M, Hasegawa N, Betsuyaku T, Iwakura Y, Tateda K, Yamaguchi K.
  • Journal Title: Infect Immun. Volume: 80 Pages: 1121-1127
  • Peer Reviewed
• [Journal Article] CRTH2 is a critical regulator of neutrophil migration and resistance to polymicrobial sepsis. (2012)
  • Author(s): Ishii M, Asano K, ...Kunkel SL, Hasegawa N, Betsuyaku T.
  • Journal Title: J Immunol Volume: 188 Pages: 5655-5664
  • Peer Reviewed
• [Presentation] Critical roles of the polycomb protein Ezh2 during influenza A virus infection (2014)
  • Author(s): Ishii M, Yagi K, Namkoong H, Fujii H, Asami T, Tasaka S, Hasegawa N, Kunkel SL, Betsuyaku T
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Clarithromycin expands CD11b+Gr-1+ cells to protect against LPS-induced lethal shock. (2014)
  • Author(s): Namkoong H, Ishii M, Fujii H, Asami T, Yagi K, Fujiwara H, Saito F, Tasaka S, Hasegawa N, Koyasu S, Betsuyaku T.
  • Organizer: The 37th Annual Conference on Shock
  • Place of Presentation: 米国 シャーロット
  • Year and Date: 2014-06-07 – 2014-06-10
• [Presentation] Critical Roles Of Enhancer Of Zeste Homolog 2(EZH2) During Influenza A Virus Infection. (2014)
  • Author(s): Yagi K, Ishii M, Namkoong H, Asami T, Fujiwara H, Nishimura T, Saito F, Tasaka S, Kunkel SL, Hasegawa N, Betsuyaku T.
  • Organizer: The 110th annual International Conference of American thoracic society
  • Place of Presentation: 米国 サンフランシスコ
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] Obesity Worsens The Outcome Of Influenza Virus Infection Via Impaired Ifn -Beta Induction In Mice. (2014)
  • Author(s): Namkoong H, Ishii M, Fujii H, Asami T, Yagi K, Saito F, Fujiwara F, Tasaka S, Hasegawa N, Betsuyaku T.
  • Organizer: The 110th annual International Conference of American thoracic society
  • Place of Presentation: 米国 サンフランシスコ
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] Clinical and bacteriological evaluations during observation of Mycobacterium avium complex lung disease without treatment. (2014)
  • Author(s): Kimizuka Y, Ishii M, Hoshino Y, Asami T, Nishimura T, Maeda S, Tasaka S, Namkoong H, Fujiwara H, Funatsu Y, Yagi K, Abe T, Iwata S, Betsuyaku T, Hasegawa N.
  • Organizer: The 110th International Conference of American Thoracic Society
  • Place of Presentation: 米国 サンフランシスコ
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] 肺炎球菌感染モデルマウスにおける間葉系幹細胞の投与効果 (2014)
  • Author(s): 浅見貴弘、石井誠、南宮湖、八木一馬、藤原宏、西村知泰、斎藤 史武、田坂 定智、長谷川直樹、別役 智子
  • Organizer: 第54回日本呼吸器学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] 肺炎球菌感染による炎症はエラスターゼ誘導肺気腫マウスでは亢進し，肺気腫を進行させる (2014)
  • Author(s): 高橋左枝子、石井誠、浅見 貴弘、八木一馬、南宮湖、原口水葉、佐々木衛、佐藤美奈子、亀山直史、山本美由紀、別役 智子
  • Organizer: 第54回日本呼吸器学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] 無治療経過観察を受けた肺Mycobacterium avium complex症患者の臨床的および細菌学的検討 (2014)
  • Author(s): 君塚善文、長谷川直樹、星野 仁彦、石井誠、西村知泰、浅見貴弘、田坂定智、南宮湖、藤原宏、舩津洋平、八木一馬、阿部貴行、前田伸司、岩田敏、別役 智子
  • Organizer: 第54回日本呼吸器学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] インフルエンザウイルス感染症におけるヒストンメチル化酵素EZH2阻害剤：3-deazaneplanocin A（DZNep）の投与効果の検討 (2014)
  • Author(s): 八木一馬、石井誠、溝口孝輔、南宮湖、浅見貴弘、藤原宏、西村知泰、斎藤史武、田坂定智、長谷川直樹、別役智子
  • Organizer: 第54回日本呼吸器学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] Obesity worsens the outcome of influenza virus infection via impaired IFN-beta induction in mice (2014)
  • Author(s): Namkoong H, Ishii M, Fujii H、Asami1 T、Yagi K、Saito F、Fujiwara H、Tasaka S、Hasegawa N、Betsuyaku T
  • Organizer: 第54回日本呼吸器学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] Prostaglandin D2 Receptor CRTH2 Is A Critical Regulator of Neutrophil Migration and Resistance to Polymicrobial Sepsis. (2013)
  • Author(s): Ishii M, Asano K, Namkoong H, Tasaka S, Asami T, Miyata J, Yagi K, Saito F, Nakamura M, Hirai H, Nagata K, Hasegawa N, and Betsuyaku T.
  • Organizer: The 28th international congress of chemotherapy and infection
  • Place of Presentation: 横浜
• [Presentation] Clarithromycin Expands CD11b+Gr-1+ cells To Protect against LPS-Induced Lethal Shock and Polymicrobial Sepsis (2013)
  • Author(s): Namkoong H, Ishii M, Fujii H, Asami T, Yagi K, Fujiwara H , Saitoh F, Tasaka S, Hasegawa N, Koyasu S, Betsuyaku T.
  • Organizer: The 28th international congress of chemotherapy and infection.
  • Place of Presentation: 横浜
• [Presentation] Mesenchymal Stem Cell-Conditioned Medium Modulates Murine Macrophage Cytokine Expression Induced by TLR7/8 Ligand Stimulation and Influenza A Virus Infection. (2013)
  • Author(s): Asami T, Ishii M, Fujii H, Namkoong H, Yagi K, Ishida Y, Funatsu Y, Kimizuka Y, Fujiwara H, Tasaka S, Hasegawa N, Betsuyaku T.
  • Organizer: The 109th annual International Conference of American thoracic society.
  • Place of Presentation: 米国 フィラデルフィア
• [Presentation] Effects of Histone Deacetylase Inhibitor Trichostatin A During Influenza A Virus Infection In Vivo And In Vitro (2013)
  • Author(s): Yagi K, Ishii M, Fujii H, Mizoguchi K, Namkoong H, Asami T, Funatsu Y, Fujiwara H, Saito F, Tasaka S, Kunkel SL, Hasegawa N, Betsuyaku T.
  • Organizer: The 109th annual International Conference of American thoracic society.
  • Place of Presentation: 米国 フィラデルフィア
• [Presentation] Clarithromycin Expands CD11b+Gr-1+ cells To Protect against LPS-Induced Lethal Shock and Polymicrobial Sepsis. (2013)
  • Author(s): Namkoong H, Ishii M, Fujii H, Asami T, Yagi K, Funatsu Y, Fujiwara H, Saitoh F, Tasaka, S, Hasegawa N, Koyasu S, Betsuyaku T.
  • Organizer: The 109th annual International Conference of American thoracic society.
  • Place of Presentation: 米国 フィラデルフィア
• [Presentation] In Vitro Effect Of 14-Hydroxy Clarithromycin, A Major Metabolite Of Clarithromycin, On Cytokine Expressions In Murine Macrophages And Dendritic Cells During Influenza A Virus Infection. (2013)
  • Author(s): Matsui Y, Ishii M, Namkoong H, Fujii H, Asami T, Yagi K, Saito F, Funatsu Y, Fujiwara H, Tasaka S, Hasegawa N, Betsuyaku T.
  • Organizer: The 109th annual International Conference of American thoracic society.
  • Place of Presentation: 米国 フィラデルフィア
• [Presentation] Diet-induced obesity modulates the macrophage response to influenza virus infection. (2013)
  • Author(s): Nakagawa T, Ishii M, Namkoong H, Fujii H, Asami T, Yagi K, Saito F, Funatsu Y, Fujiwara H, Tasaka S, Hasegawa N, Betsuyaku T.
  • Organizer: The 109th annual International Conference of American thoracic society.
  • Place of Presentation: 米国 フィラデルフィア
• [Presentation] Causes and treatment of exacerbation in COPD. Post graduate course. Change of evaluation of severity in COPD. (2013)
  • Author(s): Ishii M, Takahashi S, Betsuyaku T.
  • Organizer: The 18th annual congress of Asian Pacific Society of Respirology.
  • Place of Presentation: 横浜
  • Invited
• [Presentation] 腹膜炎誘発敗血症マウスにおけるプロスタグランジンD2受容体CRTH2の役割に関する検討。 (2012)
  • Author(s): 石井誠, 浅野浩一郎, 南宮湖, 君塚善文, 舩津洋平, 加川志津子, 宮田純, 中村正孝, 平井博之, 永田欽也, 田坂定智, 長谷川直樹, 別役智子。
  • Organizer: 第86回日本感染症学会総会
  • Place of Presentation: 長崎
• [Presentation] Prostaglandin D2 Receptor CRTH2 Is A Critical Regulator in A Mice Model of Polymicrobial Sepsis. (2012)
  • Author(s): Ishii M, Asano K, Namkoong H, Tasaka S, Miyata J, Nakamura M, Hirai H, Nagata K, Hasegawa N, and Betsuyaku T.
  • Organizer: 第41回日本免疫学会学術集
  • Place of Presentation: 神戸