sPLA_2-III, a mast cell-derived anaphylactic sPLA_2, regulates mast cell-dependent anaphylactic responses

2010 Fiscal Year Final Research Report

• Project/Area Number: 21790093
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Biological pharmacy
• Research Institution: 財団法人東京都医学研究機構 (2010); Tokyo Metropolitan Organization for Medical Research (2009)
• Principal Investigator: TAKETOMI Yoshitaka 財団法人東京都医学研究機構, 東京都臨床医学総合研究所, 主任研究員 (40365804)
• Project Period (FY): 2009 – 2010
• Keywords: アレルギー / マスト細胞 / ホスホリパーゼA_2

Research Abstract

A major allergen in honeybee venom, a potent inducer of anaphylaxis, is a secreted PLA_2 (sPLA_2) that is classified into group III, and mammalian genome encodes its endogenous homolog, sPLA_2-III. Here, we demonstrate that sPLA_2-III is expressed in mast cells and acts as a regulator of maturation and activation of mast cells and thereby of mast cell-associated anaphylactic responses. Administration of recombinant sPLA_2-III into mouse ears induced mast cell activation. Mast cell-associated active and passive anaphylactic responses were markedly attenuated in Pla2g3-knockout mice as compared with those in wild-type mice, and bone marrow-derived mast cells (BMMC) from Pla2g3-deficient mice displayed reduced histamine and lipid mediator releases. Pla2g3-null BMMC failed to reconstitute the anaphylactic response after transplantation into mast cell-deficient mice, indicating that the defects caused by Pla2g3 deficiency is mast cell autonomous. Dermal mast cells in Pla2g3-null mice were numerically normal but morphologically immature, and showed impaired degranulation. Moreover, Pla2g3-null BMMC exhibited defective fibloblast-directed maturation in vitro. Interestingly, knockout mice for a prostanoid-biosynthetic enzyme or for a receptor also displayed similar mast cell abnormalities to Pla2g3-null mice, suggesting their functional linkage. Taken together, we conclude that sPLA_2-III is the only sPLA2 isoform involved in maturation and activation of mast cells. sPLA_2-III released from immature mast cells may act on microenvironmental fibroblasts to produce particular lipid metabolites, which may in turn promote terminal maturation of mast cells.

Research Products

• [Journal Article] Secreted phospholipase A_2, Lipoprotein hydrolysis, and atherosclerosis: integration with lipidomics. (2011)
  • Author(s): Yamamoto K, Isogai Y, Sato H, Taketomi Y, Murakami M.
  • Journal Title: Anal Bioanal Chem 400 Pages: 1829-1842
  • Peer Reviewed
• [Journal Article] Hair follicular expression and function of group X secreted phospholipase A_2 in mouse skin. (2011)
  • Author(s): Yamamoto K, Taketomi Y, Isogai Y, Miki Y, Sato H, Masuda S, Nishito Y, Morioka K, Ishimoto Y, Suzuki N, Yokoya Y, Hanasaki K, Ishikawa Y, Ishii T, Kobayashi T, Fukami K, Ikeda K, Nakanishi H, Taguchi R, Murakami M.
  • Journal Title: J Biol Chem 286 Pages: 11616-11631
  • Peer Reviewed
• [Journal Article] Physiological roles of group X secreted phospholipase A_2 in reproduction, gastrointestinal phospholipid digestion, and neuronal function. (2011)
  • Author(s): Sato H, Isogai Y, Masuda S, Taketomi Y, Miki Y, Kamei D, Hara S, Kobayashi T, Ishikawa Y, Ishii T, Ikeda K, Taguchi R, Ishimoto Y, Suzuki N, Yokota Y, Hanasaki K, Suzuki-Yamamoto T, Yamamoto K, Murakami M.
  • Journal Title: J Biol Chem 286 Pages: 11632-11648
  • Peer Reviewed
• [Journal Article] Lipid networks in mast cell biology. (2011)
  • Author(s): Taketomi Y, Murakami M.
  • Journal Title: Yakugaku Zasshi Review 131 Pages: 73-84
  • Peer Reviewed
• [Journal Article] Recent progress in phospholipase A_2 research : from cells to animals to humans. (2011)
  • Author(s): Murakami M, Taketomi Y, Miki Y, Sato H, Hirabayashi T, Yamamoto K.
  • Journal Title: Prog Lipid Res 50 Pages: 152-192
  • Peer Reviewed
• [Journal Article] Mitochondrial dysfunction and reduced prostaglandin synthesis in skeletal muscle of group VIB Ca^<2+>-indpendent phospholipase A_2 (iPLA_<2У>) deficient mice. (2010)
  • Author(s): Yoda E, Hachisu K, Taketomi Y, Yoshida K, Nakamura M, Ikeda K, Taguchi R, Nakatani Y, Kuwata H, Murakami M, Kudo I, Hara S.
  • Journal Title: J Lipid Res 51 Pages: 3003-3015
  • Peer Reviewed
• [Journal Article] (2010)
  • Author(s): Escoffier J, Jemel I, Tanemoto A, Taketomi Y, Payre C, Coatrieux C, Sato H, Yamamoto K, Masuda S, Pernet-Gallay K, Pierre V, Hara S, Murakami M, De Waard M, Lambeau G, Arnoult C.
  • Journal Title: J Clin Invest 120 Pages: 1415-1428
  • Peer Reviewed
• [Journal Article] Group III secreted phospholipase A_2 regulates epididymal sperm maturation and fertility in mice. (2010)
  • Author(s): Sato H, Taketomi Y, Isogai Y, Miki Y, Yamamoto K, Masuda S, Hosono T, Arata S, Ishikawa Y, Ishii T, Kobayashi T, Nakanishi H, Ikeda K, Taguchi R, Hara S, Kudo I, Murakami M.
  • Journal Title: J Clin Invest 120 Pages: 1400-1414
  • Peer Reviewed
• [Journal Article] Emerging roles of secreted phospholipase A_2 enzymes : lessons from transgenic and knockout mice (2010)
  • Author(s): Murakami M, Taketomi Y, Girard G, Yamamoto K, Lambeau G.
  • Journal Title: Biochimie 92 Pages: 561-582
  • Peer Reviewed
• [Journal Article] ホスホリパーゼA_2の生理的・病理的役割 (2010)
  • Author(s): 村上誠, 佐藤弘泰, 平林哲也, 山本圭, 武富芳隆
  • Journal Title: 実験医学 28 Pages: 114-125
• [Journal Article] 分泌性ホスホリパーゼA_2遺伝子改変マウス (2010)
  • Author(s): 武富芳隆, 村上誠
  • Journal Title: The Lipid 121 Pages: 4-12
• [Journal Article] Group III secreted phospholipase A_2 transgenic mice spontaneously develop inflammation. (2009)
  • Author(s): Sato H, Taketomi Y, Isogai Y, Masuda S, Kobayashi T, Yamamoto K, Murakami M.
  • Journal Title: Biochem J 421 Pages: 17-27
  • Peer Reviewed
• [Journal Article] アレルギー性疾患における脂質メディエーターの役割 (2009)
  • Author(s): 武富芳隆, 佐藤弘泰, 村上誠
  • Journal Title: 実験医学 27 Pages: 2074-2079
• [Presentation] Suppression of sperm fertility by monophthalate via inhibiting spermatozoal phospholipase A_2 activity. (2011)
  • Author(s): Hara S, Taketomi Y, Sato H, Murakami M.
  • Organizer: SOT Annual Meeting
  • Place of Presentation: Washington DC, USA
  • Year and Date: 20110306-20110310
• [Presentation] Recent insights into the multiple molecular and functional properties of group X sPLA_2. (2010)
  • Author(s): Lambeau G, Jemel J, Escoffier J, Ait-Oufella H, Hiromi Li H, Guillaume C, Gora S, Surrel F, Coatrieux C, Payre C, Tanemoto A, Taketomi Y, Sato H, Yamamoto K, Arnoult C, Mallat Z, Gelb MH, Deregnaucourt C, Ninio E, Karabina S, Murakami M.
  • Organizer: 7th GERLI Lipidmics Congress.
  • Place of Presentation: Anglet-Biarritz, France
  • Year and Date: 20101003-20101006
• [Presentation] An epidermal secreted phospholipase A_2 : roles of group IIF phospholipase A_2 in skin pathophysiology. (2010)
  • Author(s): Yamamoto K, Takemomi Y, Miki Y, Shimo K, Nakanishi H, Ikeda K, Taguchi R, Gelb MH, Murakami M.
  • Organizer: FASEB Summer Research Conferences on Phospholipid Metabolism.
  • Place of Presentation: Steamboat Springs, USA
  • Year and Date: 20100627-20100702
• [Presentation] A dendritic cell secreted phospholipase A_2 : roles of group IID phospholipase A_2 in resolution of inflammation. (2010)
  • Author(s): Miki Y, Yamamoto K, Shimo K, Taketomi Y, Nakanishi H, Taguchi R, Gelb MH, Hara S, Murakami M.
  • Organizer: FASEB Summer Research Conferences on Phospholipid Metabolism.
  • Place of Presentation: Steamboat Springs, USA
  • Year and Date: 20100627-20100702
• [Presentation] Group III secreted phospholipase A_2 regulates mast cell maturation and functions. (2010)
  • Author(s): Taketomi Y, Murakami, M.
  • Organizer: Keystone Symposia.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100607-20100611
• [Presentation] Group III secreted phospholipase A_2 regulates epididymal sperm maturation and fertility in mice. (2010)
  • Author(s): Sato H, Taketomi Y, Yamamoto K, Murakami M.
  • Organizer: Keystone Symposia.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100607-20100611
• [Presentation] Roles of group IIF epidermal phospholipase A_2 in skin homeostasis and pathology. (2010)
  • Author(s): Yamamoto K, Takemomi Y, Miki Y, Shimo K, Nakanishi H, Ikeda K, Taguchi R, Gelb MH, Murakami M.
  • Organizer: Keystone Symposia.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100607-20100611
• [Presentation] Group IID secreted phospholipase A_2 is expressed in dendritic cells and plays a role in resolution of inflammation. (2010)
  • Author(s): Miki Y, Yamamoto K, Shimo K, Taketomi Y, Nakanishi H, Taguchi R, Gelb MH, Murakami M.
  • Organizer: Keystone Symposia.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100607-20100611
• [Presentation] Recent insights into the multiple molecular and functional properties of group X sPLA_2. (2010)
  • Author(s): Lambeau G, Jemel J, Escoffier J, Ait-Oufella H, Hiromi Li H, Guillaume C, Gora S, Surrel F, Coatrieux C, Payre C, Taketomi Y, Sato H, Yamamoto K, Arnoult C, Mallat Z, Gelb MH, Deregnaucourt C, Ninio E, Karabina S, Murakami M.
  • Organizer: Keystone Symposia.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100607-20100611
• [Presentation] sPLA_2-III, a mast cell-derived anaphylactic sPLA2, regulates mast cell-dependent anaphylactic response. (2010)
  • Author(s): 武富芳隆, 佐藤弘泰, 田中智之, 中村雅典, 上野紀子, 西藤泰昌, 山本圭, 杉本幸彦, 原俊太郎, 村上誠
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] sPLA_2-V, an adipocyte-inducible metabolic sPLA_2, controls systemic lipid metabolism. (2010)
  • Author(s): 佐藤弘泰, 武富芳隆, 山本圭, 石川由紀雄, 石井寿晴, 原俊太郎, 村上誠
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] sPLA_2-IIF, an epidermal sPLA_2, regulates epidermal homeostasis and pathology. (2010)
  • Author(s): 山本圭, 下華奈子, 三木寿美, 武富芳隆, 池田和貴, 中西広樹, 田口良, 村上誠
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-10
• [Presentation] sPLA_2-IID, a dendritic cell-derived resolving sPLA2, plays a role in resolution of inflammation (2010)
  • Author(s): 三木寿美, 山本圭, 下華奈子, 武富芳隆, 中西広樹, 田口良, 村上誠
  • Organizer: BMB2010
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-09
• [Presentation] New insights into the functions of secreted phospholipase A_2s : sPLA_2 in reproduction. (2010)
  • Author(s): Sato H, Taketomi Y, Yamamoto K, Arnoult C, Lambeau G, Murakami M.
  • Organizer: 7^<th> GERLI Lipidmics Congress.
  • Place of Presentation: Anglet-Biarritz, France
  • Year and Date: 2010-10-05
• [Presentation] Secreted phospholipase A_2, lipid mediators, and immunity. (2010)
  • Author(s): Murakami M, Taketomi Y, Yamamoto K.
  • Organizer: 14^<th> International Congress of Inflammation.
  • Place of Presentation: Kobe, Japan
  • Year and Date: 2010-08-27
• [Presentation] リピドミクスの生化学への適用:マスト細胞の分化成熟と活性化におけるリン脂質組成の包括的解析 (2010)
  • Author(s): 上野紀子, 武富芳隆, 池田和貴, 山本圭, 村上誠, 田口良
  • Organizer: 第58回脂質分析総合討論会
  • Place of Presentation: 筑波
  • Year and Date: 2010-06-18
• [Presentation] III型分泌性ホスホリパーゼA_2の欠損はメタボリックシンドロームを改善する (2010)
  • Author(s): 佐藤弘泰, 磯貝有紀, 武富芳隆, 山本圭, 石川由紀雄, 石井壽晴, 小林哲幸, 中西広樹, 池田和貴, 田口良, 原俊太郎, 村上誠
  • Organizer: 第52回脂質生化学会
  • Place of Presentation: 伊香保
  • Year and Date: 2010-06-15
• [Presentation] 皮膚特異的分泌性ホスホリパーゼA_2の病態生理機能 (2010)
  • Author(s): 山本圭, 武富芳隆, 三木寿美, 下華奈子, 池田和貴, 中西広樹, 田口良, Gelb MH, 村上誠
  • Organizer: 第52回脂質生化学会
  • Place of Presentation: 伊香保
  • Year and Date: 2010-06-15
• [Presentation] マスト細胞研究の新展開マスト細胞における脂質ネットワーク (2010)
  • Author(s): 武富芳隆, 村上誠
  • Organizer: 日本薬学会第130年会,【招待講演】
  • Place of Presentation: 岡山
  • Year and Date: 2010-03-28
• [Presentation] 新生期マウスの呼吸馴化における系統の差異 (2009)
  • Author(s): 荒田悟, 荒田晶子, 武富芳隆, 細野知彦, 鬼丸洋, 塩田清二
  • Organizer: 第56回日本実験動物学会総会
  • Place of Presentation: 埼玉
  • Year and Date: 20090514-20090516
• [Presentation] 樹状細胞に発現しているIID型分泌性ホスホリパーゼA_2の解析 (2009)
  • Author(s): 三木寿美, 山本圭, 武富芳隆, Gelb MH, 原俊太郎, 村上誠
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-24
• [Presentation] III型分泌性ホスホリパーゼA_2はマスト細胞の分化成熟に関与する (2009)
  • Author(s): 武富芳隆, 佐藤弘泰, 田中智之, 上野紀子, 山本圭, 原俊太郎, 村上誠
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-22
• [Presentation] III型分泌性ホスホリパーゼA_2は精子成熟を制御する (2009)
  • Author(s): 佐藤弘泰, 武富芳隆, 磯貝有紀, 山本圭, 三木寿美, 小林哲幸, 池田和貴, 中西広樹, 田口良, 原俊太郎, 村上誠
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-22
• [Presentation] IIF型ホスホリパーゼA_2の皮膚生理機能 (2009)
  • Author(s): 山本圭, 武富芳隆, 三木寿美, 中西広樹, 池田和貴, 西藤泰昌, Gelb MH, 田口良, 村上誠
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-22
• [Presentation] 脂肪組織における膜結合型Ca^<2+>非依存性ホスホリパーゼA_2(iPLA_<2γ>)の機能解析 (2009)
  • Author(s): 依田恵美子, 鉢須桂子, 武富芳隆, 原俊太郎
  • Organizer: 第82回日本生化学会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-22
• [Presentation] III型分泌性ホスホリパーゼA_2はマスト細胞依存性の即時型アレルギーに関わる (2009)
  • Author(s): 武富芳隆, 佐藤弘泰, 田中智之, 上野紀子, 山本圭, 田口良, 工藤一郎, 原俊太郎, 村上誠
  • Organizer: 第51回日本脂質生化学会
  • Place of Presentation: 愛知
  • Year and Date: 2009-07-31
• [Presentation] マスト細胞におけるリン脂質代謝の網羅解析 (2009)
  • Author(s): 上野紀子, 山本圭, 武富芳隆, 池田和貴, 田口良, 村上誠
  • Organizer: 第51回日本脂質生化学会
  • Place of Presentation: 愛知
  • Year and Date: 2009-07-31
• [Presentation] III型分泌性ホスホリパーゼA_2は精子成熟を制御する (2009)
  • Author(s): 佐藤弘泰, 武富芳隆, 磯貝有紀, 山本圭, 三木寿美, 石川由紀雄, 石井壽晴, 小林哲幸, 中西広樹, 池田和貴, 田口良, 工藤一郎, 原俊太郎, 村上誠
  • Organizer: 第51回日本脂質生化学会
  • Place of Presentation: 愛知
  • Year and Date: 2009-07-31
• [Presentation] 皮膚特異的分泌性ホスホリパーゼA_2の機能解析 (2009)
  • Author(s): 山本圭, 武富芳隆, 三木寿美, 池田和貴, 中西広樹, 田口良, 工藤一郎, 村上誠
  • Organizer: 第51回日本脂質生化学会
  • Place of Presentation: 愛知
  • Year and Date: 2009-07-31
• [Presentation] 膜結合型カルシウム非依存性ホスホリパーゼA_2(iPLA_<2γ>)の生体内機能解析 (2009)
  • Author(s): 依田恵美子, 鉢須桂子, 武富芳隆, 村上誠, 原俊太郎
  • Organizer: 第51回日本脂質生化学会
  • Place of Presentation: 愛知
  • Year and Date: 2009-07-31
• [Presentation] Group III phospholipase A_2, an endogenous bee venom phospholipase A_2 homolog, is a regulator of mast cell maturation and functions. (2009)
  • Author(s): Taketomi Y, Sato H, Tanaka S, Otsuka H, Yamamoto K, Nakamura M, Sugimoto Y, Kudo I, Hara S, Murakami M.
  • Organizer: WCI2009.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2009-07-07
• [Presentation] Group III phospholipase A_2, an endogenous bee venom phospholipase A_2 homolog, is a crucial regulator of mast cell maturation and functions. (2009)
  • Author(s): Taketomi Y, Sato H, Ueno N, Yamamoto K, Murakami M.
  • Organizer: PLM2009.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2009-05-17
• [Presentation] Impaired sperm maturation and fertility in group III phospholipase A_2-deficient mice. (2009)
  • Author(s): Sato H, Taketomi Y, Isogai Y, Yamamoto K, Murakami M.
  • Organizer: PLM2009.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2009-05-17
• [Presentation] Group III phospholipase A_2 in stromal fraction of adipose tissue controls systemic lipid homeostasis. (2009)
  • Author(s): Isogai Y, Sato H, Taketomi Y, Yamamoto K, Kobayashi T, Murakami M.
  • Organizer: PLM2009.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2009-05-17
• [Presentation] Group IIF phospholipase A_2 : An epidermal secreted phospholipase A_2. (2009)
  • Author(s): Yamamoto K, Taketomi Y, Miki Y, Nakanishi H, Ikeda K, Nishito Y, Suzuki H, Taguchi R, Murakami M.
  • Organizer: PLM2009.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2009-05-17
• [Presentation] Group IID phospholipase A_2 : A dendritic cell secreted phospholipase A2. (2009)
  • Author(s): Miki Y, Yamamoto K, Taketomi Y, Murakami M.
  • Organizer: PLM2009.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2009-05-17
• [Presentation] Analysis of group VIB Ca^<2+>-independent phospholipase A_2 (iPLA_2.)-deficient mice. (2009)
  • Author(s): Yoda E, Hachisu K, Taketomi Y, Murakami M, Kudo I, Hara S.
  • Organizer: PLM2009.
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2009-05-17
• [Book] 高脂血症.生命科学研究の戦略:疾患モデルマウスと表現型解析 (2011)
  • Author(s): 佐藤弘泰, 武富芳隆, 山本圭, 村上誠
  • Publisher: 中山書店(印刷中)
• [Book] Obstructive Airway Diseases: Role of Lipid Mediators.Talor & Francis (2011)
  • Author(s): Taketomi Y, Murakami M.
  • Publisher: Phospholipase A_2 as a potential drug target for airway disorders.(in press)
• [Remarks] 【論文(7)(8)】プレス発表:ScienceDaily."New requirements for male fertility" (April 27, 2010)
  • URL: http://www.sciencedaily.com/releases/2010/04/100426181710.htm