Construction of foundation on the function of the immune suppressive sPLA2 and toward its drug discovery

• Project/Area Number: 26860051
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Biological pharmacy
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: MIKI Yoshimi 公益財団法人東京都医学総合研究所, 生体分子先端研究分野, 研究員 (00632499)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 脂質 / ホスホリパーゼ / 抗炎症 / 皮膚疾患 / 免疫 / オメガ3 / 樹状細胞 / マクロファージ / DHA / 癌 / ホスホリパーゼA2 / 脂肪酸 / レゾルビン

Outline of Final Research Achievements

In this study, we showed that psoriasis was exacerbated in Pla2g2d-null mice, whereas it was ameliorated in Pla2g2d-overexpressing transgenic mice, relative to littermate wild-type mice. These phenotypes were associated with concomitant alterations in the tissue levels of omega-3 polyunsaturated fatty acid (PUFA) metabolites, which had the capacity to reduce the expression of Th17-type cytokines in dendritic cells or lymph node cells. In the context of cancer, however, Pla2g2d deficiency resulted in marked attenuation of skin carcinogenesis, likely because of the augmented anti-tumor immunity. Altogether, these results underscore a general role of sPLA2-IID as an immunosuppressive sPLA2 that allows the microenvironmental lipid balance toward an anti-inflammatory state, exerting beneficial or detrimental impact depending upon distinct pathophysiological contexts in inflammation and cancer.

Research Products

• [Int'l Joint Research] University of Washington(米国)
• [Int'l Joint Research] Universite de Nice-Sophia-Antipolis(France)
• [Journal Article] The role of group IIF secreted phospholipase A2 in epidermal homeostasis and hyperplasia. (2015)
  • Author(s): Yamamoto, K., Miki, Y., Sato, M., Taketomi, Y., Nishito, Y., Taya, C., Muramatsu, K., Ikeda, K., Nakanishi, H., Taguchi, R., Kambe, N., Kabashima, K., Lambeau, G., Gelb, M.H., and Murakami, M
  • Journal Title: J. Exp. Med. Volume: 212 Issue: 11 Pages: 1901-1919
  • DOI: 10.1084/jem.20141904
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Critical role of Phospholipase A2 group IID in age-related susceptibility to Severe Acute Respiratory Syndrome-CoV infection. (2015)
  • Author(s): Vijay, R., Hua, X., Meyerholz, D.K., Miki, Y., Yamamoto, K., Gelb, M.H., Murakami, M., and Perlman, S.
  • Journal Title: J. Exp. Med. Volume: 212 Issue: 11 Pages: 1851-1868
  • DOI: 10.1084/jem.20150632
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 接触皮膚炎と抗炎症脂質メディエーター (2015)
  • Author(s): 三木 寿美、山本 圭、村上 誠
  • Journal Title: 臨床免疫・アレルギー科 Volume: 63 Pages: 156-163
  • Peer Reviewed
• [Journal Article] Emerging roles of secreted phospholipase A2 enzymes: the 3rd edition. (2014)
  • Author(s): Murakami M, Taketomi Y, Miki Y, Sato H, Yamamoto K, Lambeau G.
  • Journal Title: Biochimie Volume: 107Pt A Pages: 105-113
  • DOI: 10.1016/j.biochi.2014.09.003
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The adipocyte-inducible secreted phospholipases PLA2G5 and PLA2G2E play distinct roles in obesity. (2014)
  • Author(s): Sato H, Taketomi Y, Ushida A, Isogai Y, Kojima T, Hirabayashi T, Miki Y, Yamamoto K, Nishito Y, Kobayashi T, Ikeda K, Taguchi R, Hara S, Ida S, Miyamoto Y, Watanabe M, Baba H, Miyata K, Oike Y, Gelb MH, Murakami M.
  • Journal Title: Cell Metab. Volume: 20 Issue: 1 Pages: 119-132
  • DOI: 10.1016/j.cmet.2014.05.002
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 癌病態におけるIID型分泌性ホスホリパーゼA2の役割 (2015)
  • Author(s): 城戸口優, 山本圭, 三木寿美, 村上誠
  • Organizer: BMB2015
  • Place of Presentation: 神戸ポートアイランド（兵庫県神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Plasmalogen-lysophosphatidylethanolamine driven by group IIF sPLA2 underlies epidermal-hyperplasic disorders (2015)
  • Author(s): Yamamoto K, Miki Y, Taketomi Y, Kambe N, Kabashima K, Lambeau G, Gelb MH, and Murakami M
  • Organizer: The 14th International Conference on Bioactive Lipids in Inflammation, Cancer and Related Diseases
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2015-07-12
• [Presentation] IF型分泌性ホスホリパーゼA2により産生されるアルケニル型リゾホスファチジルエタノールアミンは表皮肥厚性疾患の新規バイオマーカーである (2015)
  • Author(s): 山本圭, 三木寿美, 村上誠
  • Organizer: 第57回日本脂質生化学会
  • Place of Presentation: 一橋大学一橋講堂（東京都千代田区）
  • Year and Date: 2015-05-28
• [Presentation] IID型分泌性ホスホリパーゼA2は乾癬を抑制する (2015)
  • Author(s): 三木 寿美、山本 圭、村上 誠
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 神戸学院大学・兵庫医療大学・神戸サンボーホール・デザイン・クリエイティブセンター神戸、兵庫県・神戸市
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Group IID phospholipase sPLA2 resolves psoriasis by driving antiinflammatory pro-resolving lipid mediators. (2015)
  • Author(s): Miki, Y., Yamamoto, K., and Murakami, M.
  • Organizer: The 6th international conference on Phospholipase A2 and Lipid Mediators from bench to translational medicine.
  • Place of Presentation: Keio Plaza Hotel Tokyo, Shinjuku-Ku, Tokyo, Japan
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] New insights into PLA2s: from outside and inside. (2015)
  • Author(s): Murakami, M., Taketomi1, Y., Sato, H., Miki, Y., Hirabayashi, T., and Yamamoto, K.
  • Organizer: The 6th international conference on Phospholipase A2 and Lipid Mediators from bench to translational medicine.
  • Place of Presentation: Keio Plaza Hotel Tokyo, Shinjuku-Ku, Tokyo, Japan
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] A unique lipid pathway driven by group IIF sPLA2 undelies epidermal-hyperplasic disorders. (2015)
  • Author(s): Yamamoto, K., Miki, Y., Taketomi, Y., Kambe, N., Kabashima, K., Lambeau, G., Gelb, M. H., and Murakami, M.
  • Organizer: The 6th international conference on Phospholipase A2 and Lipid Mediators from bench to translational medicine.
  • Place of Presentation: Keio Plaza Hotel Tokyo, Shinjuku-Ku, Tokyo, Japan
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] Group IIF sPLA2 promotes skin carcinogenesis. (2015)
  • Author(s): Yamamoto, K., Miki, Y., Sato, M., and Murakami, M.
  • Organizer: The 6th international conference on Phospholipase A2 and Lipid Mediators from bench to translational medicine.
  • Place of Presentation: Keio Plaza Hotel Tokyo, Shinjuku-Ku, Tokyo, Japan
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] Phospholipase A2 and Lipid Mediators in Health and Disease. (2014)
  • Author(s): Murakami, M., Taketomi, Y., Sato, H., Miki, Y., and Yamamoto, K.
  • Organizer: 2014 YONSEI BK21 PLUS-IGAKUKEN Joint Symposium ”Transnational Exchange of Science between Korea and Japan”.
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2014-06-19 – 2014-06-22
• [Presentation] Secreted phospholipase PLA2G2F regulates epidermal homeostasis and hyperplastic diseases by mobilizing unique lipid products. (2014)
  • Author(s): Yamamoto, K., Miki, Y., Taketomi, Y., Murakami, M.
  • Organizer: 2014 YONSEI BK21 PLUS-IGAKUKEN Joint Symposium ”Transnational Exchange of Science between Korea and Japan”.
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2014-06-19 – 2014-06-22
• [Remarks] 東京都医学総合研究所 脂質代謝プロジェクト（村上研究室）
  • URL: http://www.igakuken.or.jp/lipid/
• [Remarks] 東京都医学総合研究所・脂質代謝プロジェクト（村上研究室）
  • URL: http://www.igakuken.or.jp/lipid/