New insights into the roles of secreted phospholipase A2 in allergy, atherosclerosis, and cancer

• Project/Area Number: 25460087
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tokyo Metropolitan Institute of Medical Science
• Principal Investigator: TAKETOMI Yoshitaka 公益財団法人東京都医学総合研究所, 生体分子研究分野, 主席研究員 (40365804)
• Research Collaborator: MURAKAMI Makoto
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 脂質代謝 / アレルギー / 動脈硬化 / 大腸癌 / ホスホリパーゼA2 / 脂質メディエーター / 癌 / リン脂質 / 分泌性ホスホリパーゼA2 / マスト細胞成熟 / リゾホスファチジン酸 / アナフィラキシー / 好塩基球 / IgE依存性慢性アレルギー性炎症 / LDL変性

Outline of Final Research Achievements

Phosholipas A2 (PLA2) is a group of enzyme that hydrolyze the phospholipids to yield fatty acids and lysophospholipids. Here we have found that the paracrine PGD2 circuit driven by PLA2G3, a secreted PLA2 isoform, is a previously unrecognized lipid-orchestrated pathway linked to allergy and uncovers a missing microenvironmental cue underlying the proper maturation of mast cells. In addition to that, we identified the LPA-LPA1 axis as another lipid-orchestrated pathway toward mast cell maturation. Besides the regulation of mast cell and allergy, accumulating evidence suggests that PLA2G3 generally acts as a paracrine coordinator of various pathophysiological events as metabolic disorders and inflammatory bowl diseases. Our results highlight that PLA2G3 is bona fide pro-atherogenic sPLA2 that facilitates atherosclerosis through modifying LDL and promotes colitis and colon cancer by mobilizing lysophospholipids, providing a rationale for PLA2G3 to be a novel drug target of these diseases.

Research Products

• [Int'l Joint Research] University of Washington(米国)
• [Int'l Joint Research] CNRS et Universite de Nice(フランス)
• [Int'l Joint Research] Yeungnam University(韓国)
• [Int'l Joint Research] KU Leuven-University of Leuven(ベルギー)
• [Journal Article] Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility. (2016)
  • Author(s): Murase R, Sato H, Yamamoto K, Ushida A, Nishito Y, Ikeda K, Kobayashi T, Yamamoto T, Taketomi Y, Murakami M.
  • Journal Title: J Biol Chem. Volume: 291 Issue: 13 Pages: 6895-6911
  • DOI: 10.1074/jbc.m116.715672
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] NecroX-5 suppresses IgE/Ag-stimulated anaphylaxis and mast cell activation by regulating the SHP-1-Syk signaling module (2016)
  • Author(s): Li X, Kwon O, Kim DY, Taketomi Y, Murakami M, Chang HW
  • Journal Title: Allergy Volume: 71 Issue: 2 Pages: 198-209
  • DOI: 10.1111/all.12786
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Specificity of secreted phospholipase A2s for natural membrane phospholipids. Methods Enzymol. (2016)
  • Author(s): Yamamoto K, Miki Y, Sato S, Murase R, Taketomi Y, Murakami M.
  • Journal Title: Methods Enzymol Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Immunological regulation by secreted phospholipase A2. (2016)
  • Author(s): Murakami M, Yamamoto K, Miki Y, Murase R, Sato H, Taketomi Y.
  • Journal Title: Adv Immunol Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Metabolic regulation by secreted phospholipase A2. (2016)
  • Author(s): Murakami M, Taketomi Y, Sato H.
  • Journal Title: Inflamm Regener Volume: 印刷中
• [Journal Article] 分泌性ホスホリパーゼA2とアレルギー疾患. (2016)
  • Author(s): 村上誠, 三木寿美, 山本圭, 武富芳隆.
  • Journal Title: 臨床免疫・アレルギー科 Volume: 印刷中
• [Journal Article] 肥満細胞と脂質メディエーター. (2016)
  • Author(s): 武富芳隆, 村上誠.
  • Journal Title: 皮膚アレルギーフロンティア Volume: 印刷中
• [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] Phospholipase A2 group III and group X have opposing associations with prognosis in colorectal cancer. (2015)
  • Author(s): Kazama S, Kitayama J, Hiyoshi M, Taketomi Y, Murakami M, Nishikawa T, Tanaka T, Tanaka J, Kiyomatsu T, Kawai K, Hata K, Yamaguchi H, Nozawa H, Ishihara S, Sunami E, Watanabe T.
  • Journal Title: Anticancer Res Volume: 35 Pages: 2983-2990
  • Peer Reviewed
• [Journal Article] Primary cilium suppression by SREBP1c involves distortion of vesicular trafficking by PLA2G3 (2015)
  • Author(s): Gijs HL, Willemarck N, Vanderhoydonc F, Khan NA, Dehairs J, Derua R, Waelkens E, Taketomi Y, Murakami M, Agostinis P, Annaert W, Swinnen JV
  • Journal Title: Mol Biol Cell Volume: 26 Issue: 12 Pages: 2321-2332
  • DOI: 10.1091/mbc.e14-10-1472
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A New Era of Secreted Phospholipase A2 (sPLA2). (2015)
  • Author(s): Murakami M, Sato H, Miki Y, Yamamoto K, Taketomi Y.
  • Journal Title: J Lipid Res Volume: 印刷中 Issue: 7 Pages: 1248-1261
  • DOI: 10.1194/jlr.r058123
  • Peer Reviewed / Open Access
• [Journal Article] sPLA2と炎症. (2015)
  • Author(s): 武富芳隆, 村上誠.
  • Journal Title: 炎症と免疫 Volume: 23 Pages: 492-498
• [Journal Article] アレルギーと脂質代謝. (2015)
  • Author(s): 武富芳隆, 村上誠.
  • Journal Title: 臨床免疫・アレルギー科 Volume: 63 Pages: 585-592
  • NAID: 40020505111
• [Journal Article] 全身の代謝を制御するmetabolic sPLA2の発見. (2015)
  • Author(s): 佐藤弘泰, 武富芳隆, 村上誠.
  • Journal Title: 新学術領域研究「生命応答を制御する脂質マシナリー」ニュースレター Volume: 5 Pages: 24-26
• [Journal Article] Calpastatin counteracts pathological angiogenesis by inhibiting suppressor of cytokine signaling 3 degradation in vascular endothelial cells. (2015)
  • Author(s): Miyazaki, T., Taketomi, Y., Saito, Y., Hosono, T., Lei, X.F., Kim-Kaneyama, J.R., Arata, S., Takahashi, H., Murakami, M., and Miyazaki, A.
  • Journal Title: Circ. Res. Volume: 116 Issue: 7 Pages: 1170-1181
  • DOI: 10.1161/circresaha.116.305363
  • Peer Reviewed / Open Access
• [Journal Article] Secreted phospholipase A₂ and mast cells (2015)
  • Author(s): Murakami M, Taketomi Y.
  • Journal Title: Allergology International Volume: 64 Issue: 1 Pages: 4-10
  • DOI: 10.1016/j.alit.2014.07.005
  • NAID: 130004873126
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Emerging Roles of Phospholipase A₂s in Mast Cell Biology (2014)
  • Author(s): Taketomi, Y
  • Journal Title: YAKUGAKU ZASSHI Volume: 134 Issue: 11 Pages: 1179-1189
  • DOI: 10.1248/yakushi.14-00198
  • NAID: 130004712978
  • ISSN: 0031-6903, 1347-5231
  • Year and Date: 2014-11-01
  • 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] ERK1/2 antagonize AMPK-dependent regulation of FcεRI-mediated mast cell activation and anaphylaxis. (2014)
  • Author(s): Hwang, S.K., Lu, Y., Li, X., Kim, Y.D., Cho, Y.S., Jahng, Y., Son, J.K., Lee, Y.J., Kang, W., Taketomi, Y., Murakami, M., Moon, T.C., and Chang, H.W.
  • Journal Title: J. Allergy Clin. Immunol. Volume: 134 Issue: 3 Pages: 714-721
  • DOI: 10.1016/j.jaci.2014.05.001
  • Peer Reviewed / Open Access
• [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
• [Journal Article] New insights into the roles of secreted phospholipase A2s in immunity. (2014)
  • Author(s): Taketomi Y, Murakami M.
  • Journal Title: Seikagaku Volume: 86 Pages: 286-291
• [Journal Article] ホスホリパーゼA2によるマスト細胞の制御 (2014)
  • Author(s): 武富芳隆、村上誠
  • Journal Title: 臨床免疫・アレルギー科 Volume: 62 Pages: 659-667
• [Journal Article] リン脂質シグナル，PLA2と発がん (2014)
  • Author(s): 武富芳隆、村上誠
  • Journal Title: The Lipid Volume: 25 Pages: 70-78
• [Journal Article] Prostaglandin E2-EP3 signaling induces inflammatory swelling by mast cell activation. (2014)
  • Author(s): Morimoto, K., Shirata, N., Taketomi, Y., Tsuchiya, S., Segi-Nishida, E., Inazumi, T., Kabashima, K., Tanaka, S., Murakami, M., Narumiya, S., and Sugimoto, Y.
  • Journal Title: J. Immunol. Volume: 192 Issue: 3 Pages: 1130-1137
  • DOI: 10.4049/jimmunol.1300290
  • Peer Reviewed
• [Journal Article] sPLA2を起点とした脂質ネットワークによる生命応答制御 (2014)
  • Author(s): 武富芳隆, 村上誠
  • Journal Title: 医学の歩み Volume: 248 Pages: 949-955
• [Journal Article] 局所環境のPGD2を動員してアレルギーを制御するAnaphylactic sPLA2の発見 (2014)
  • Author(s): 武富芳隆, 村上誠
  • Journal Title: 新学術領域研究「生命応答を制御する脂質マシナリー」ニュースレター Volume: 4 Pages: 24-26
• [Journal Article] Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators. (2013)
  • Author(s): Miki Y, Yamamoto K, Taketomi Y, Sato H, Shimo K, Kobayashi T, Ishikawa Y, Ishii T, Nakanishi H, Ikeda K, Taguchi R, Kabashima K, Arita M, Arai H, Lambeau G, Bollinger JM, Hara S, Gelb MH, Murakami M.
  • Journal Title: J Exp Med. Volume: 210 Issue: 6 Pages: 1217-1234
  • DOI: 10.1084/jem.20121887
  • Peer Reviewed
• [Journal Article] Mast cell maturation is driven via a novel group III phospholipase A2-prostaglandin D2-DP1 receptor paracrine axis. (2013)
  • Author(s): Taketomi, Y., Morimoto, K., Murakami, M., et al., 他30名
  • Journal Title: Nature Immunol. Volume: (印刷中) Issue: 6 Pages: 554-63
  • DOI: 10.1038/ni.2586
  • Peer Reviewed
• [Journal Article] AMP-activated protein kinase negatively regulates FcεRI-mediated mast cell signaling and anaphylaxis in mice. (2013)
  • Author(s): Hwang SL, Li X, Lu Y, Jin Y, Jeong YT, Kim YD, Lee IK, Taketomi Y, Sato H, Cho YS, Murakami M, Chang HW.
  • Journal Title: J Allergy Clin Immunol. Volume: 132 Issue: 3 Pages: 729-736
  • DOI: 10.1016/j.jaci.2013.02.018
  • Peer Reviewed
• [Journal Article] 分泌性ホスホリパーゼA2 (2013)
  • Author(s): 武富芳隆, 村上誠
  • Journal Title: The Lipid Volume: 24 Pages: 70-78
• [Journal Article] 脂質メディエーターによるアレルギー制御 (2013)
  • Author(s): 武富芳隆, 村上誠
  • Journal Title: 実験医学 Volume: 31 Pages: 118-128
• [Journal Article] 脂質ネットワークとアナフィラキシー (2013)
  • Author(s): 武富芳隆, 村上誠
  • Journal Title: アレルギー・免疫 Volume: 20 Pages: 38-48
• [Presentation] 脂質メディエーターと免疫調節. (2016)
  • Author(s): 武富芳隆, 村上誠.
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-03-26
  • Invited
• [Presentation] リゾホスファチジン酸はマスト細胞の成熟に関わる. (2015)
  • Author(s): 武富芳隆, 可野邦行, 青木淳賢, 村上誠.
  • Organizer: BMB2015 (第38回日本分子生物学会年会, 第88回日本生化学会大会 合同大会)
  • 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] Skin abnormalities in group III sPLA2-deficient mice. (2015)
  • Author(s): Taketomi Y, Endo Y, Yamamoto K, Kobayashi T, Murakami M.
  • Organizer: Bioactive Lipids in Cancer, Inflammation, and Related Diseases (14th International Conference)
  • Place of Presentation: SOFITEL CHAIN BRIDGE HOTEL (Budapest, Hungary)
  • Year and Date: 2015-07-12
  • Int'l Joint Research
• [Presentation] III型分泌性ホスホリパーゼA2は皮膚バリア恒常性に関わる. (2015)
  • Author(s): 武富芳隆, 遠藤由妃, 山本圭, 小林哲幸, 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] Group III sPLA2 facilitates mast cell maturation and anaphylaxis. (2015)
  • Author(s): Taketomi Y, Ueno N, Sato S, Yamamoto K, Murakami M.
  • Organizer: 6th International Conference on Phospholipase A2 and Lipid mediators (PLM2015)
  • Place of Presentation: 京王プラザホテル、東京
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] Deficiency of group III sPLA2 protects from atherosclerosis. (2015)
  • Author(s): Taketomi Y, Miyazaki T, Sato S, Murakami M.
  • Organizer: 6th International Conference on Phospholipase A2 and Lipid mediators (PLM2015)
  • Place of Presentation: 京王プラザホテル、東京
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] Skin abnormalities in group III sPLA2-deficient mice. (2015)
  • Author(s): Endo Y, Taketomi Y, Yamamoto K, Kobayashi T, Murakami M.
  • Organizer: 6th International Conference on Phospholipase A2 and Lipid mediators (PLM2015)
  • Place of Presentation: 京王プラザホテル、東京
  • Year and Date: 2015-02-10 – 2015-02-12
• [Presentation] 脂質によるアレルギー制御の新基軸 (2014)
  • Author(s): 武富芳隆
  • Organizer: 首都大学バイオコンファレンス2014
  • Place of Presentation: 首都大学、東京
  • Year and Date: 2014-11-07
  • Invited
• [Presentation] ホスホリパーゼA2を基軸とした脂質免疫制御と疾患 (2014)
  • Author(s): 武富芳隆、村上誠
  • Organizer: 第87回日本生化学会
  • Place of Presentation: 国立京都国際会館、京都
  • Year and Date: 2014-10-15 – 2014-10-18
  • Invited
• [Presentation] ホスホリパーゼA2を基軸とした脂質免疫制御 (2014)
  • Author(s): 武富芳隆、村上誠
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 万国津梁館、沖縄
  • Year and Date: 2014-07-01 – 2014-07-04
  • Invited
• [Presentation] Phospholipase A2-driven lipid network in mast cell biology. (2014)
  • Author(s): Taketomi Y, Murakami M.
  • Organizer: 医学研・延世大学Joint Symposium, Yonsei・CBSM Joint Conference.
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2014-06-19 – 2014-06-22
• [Presentation] III型分泌性ホスホリパーゼA2は動脈硬化を制御する (2014)
  • Author(s): 武富芳隆，他3名
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本
• [Presentation] 脂質メディエーターによるアレルギー制御 (2014)
  • Author(s): 武富芳隆，村上誠
  • Organizer: 第77回日本皮膚科学会東京支部学術大会
  • Place of Presentation: 東京
  • Invited
• [Presentation] III型分泌性ホスホリパーゼA2は動脈硬化を制御する (2013)
  • Author(s): 武富芳隆，他3名
  • Organizer: 第86回日本生化学会
  • Place of Presentation: 横浜
• [Presentation] PLA2G3-PGD2 circuitはアレルギーを制御する (2013)
  • Author(s): 武富芳隆，村上誠
  • Organizer: 新学術領域研究「自然炎症」＋「脂質マシナリー」合同若手ワークショップ
  • Place of Presentation: 徳島
• [Presentation] Group III phospholipase A2 regulates mast cell maturation and anaphylaxis through a novel paracrine PGD2 loop (2013)
  • Author(s): Taketomi, Y., et al.
  • Organizer: 5th International Conference on Phospholipase A2 Mediated Signaling in Translational Medicine
  • Place of Presentation: New Orleans, LA, USA
• [Presentation] 脂質メディエーターの新機軸
  • Author(s): 武富芳隆，村上誠
  • Organizer: 第25回鹿児島呼吸器セミナー
  • Place of Presentation: 鹿児島
  • Invited
• [Presentation] PLA2を起点とした脂質ネットワークによるアレルギー制御
  • Author(s): 武富芳隆，村上誠
  • Organizer: 第23回東京免疫フォーラム
  • Place of Presentation: 東京
• [Presentation] PLA2を起点とした脂質ネットワークによるアレルギー制御
  • Author(s): 武富芳隆，村上誠
  • Organizer: 第12回ホスファチジルセリン研究会
  • Place of Presentation: 東京
  • Invited
• [Presentation] マスト細胞を制御する新たな脂質ネットワークの発見
  • Author(s): 武富芳隆
  • Organizer: 第57回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Invited
• [Book] Bioactive Lipid Mediators: Current Reviews and Protocols. Eds. by Yokomizo T and Murakami M. (2015)
  • Author(s): Murakami M, Taketomi Y.
  • Total Pages: 20
  • Publisher: Springer
• [Book] 疾患モデルの作製と利用－脂質代謝異常と関連疾患 下巻. (2015)
  • Author(s): 武富芳隆, 村上誠.
  • Total Pages: 14
  • Publisher: エル・アイ・シー
• [Remarks] 表皮細胞酵素が生理活性脂質作製し皮膚の分化・増殖促す東京都医学総研などが仕組みを発見
  • URL: http://www.nikkan.co.jp/news/nkx1020151015eaae.html
• [Remarks] 皮膚の健康と病気を調節する脂質の新しい役割の発見
  • URL: http://www.jst.go.jp/pr/announce/20151013/
• [Remarks] 皮膚の健康と病気を調節する脂質の新しい役割の発見
  • URL: http://www.igakuken.or.jp/lipid/Research/research11.html
• [Remarks] World Biomedical Frontiers
  • URL: http://biomedfrontiers.org/diabetes-obesity-2014-12-1/
• [Remarks] 脂肪細胞から分泌されるリン脂質分解酵素PLA2G5とPLA2G2Eは肥満において異なる役割を担う
  • URL: http://first.lifesciencedb.jp/archives/8936#more-8936
• [Remarks] 脂肪細胞から分泌される脂質代謝酵素による肥満の新しい調節機構の発見
  • URL: http://www.metro.tokyo.jp/INET/OSHIRASE/2014/06/20o69200.htm
• [Remarks] 肥満に関わる2種類の脂質分解酵素が明らかに
  • URL: http://www.zaikei.co.jp/article/20140607/197755.html
• [Remarks] 東京都など、肥満を改善または促進する2種類の脂質代謝酵素を発見
  • URL: http://news.mynavi.jp/news/2014/06/06/252/
• [Remarks] 体に蓄えられた魚の油が病気を止める -体に優しい脂質を動かし炎症にブレーキをかける酵素の発見-
  • URL: http://www.metro.tokyo.jp/INET/OSHIRASE/2013/05/20n5o400.htm
• [Remarks] III型ホスホリパーゼA2-プロスタグランジンD2経路はマスト細胞の成熟を制御する
  • URL: http://first.lifesciencedb.jp/archives/6996#more-6996
• [Remarks] 花粉症などのアレルギー克服に期待 -東京都、新たな脂質代謝経路を解明
  • URL: http://news.mynavi.jp/news/2013/05/01/113/index.html
• [Remarks] アレルギーを起こす新しい脂質代謝経路を解明 -花粉症等アレルギー克服に向けての新しい創薬に期待-
  • URL: http://www.metro.tokyo.jp/INET/OSHIRASE/2013/04/20n4u600.htm
• [Remarks] PLA2G3酵素、新規抗アレルギー薬の創薬標的として有望
  • URL: http://www.wic-net.com/report/2011/5.html