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マスト細胞の分化におけるヒスタミン合成酵素とプロスタノイド受容体の発現調節

Research Project

Project/Area Number 12139205
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionMukogawa Women's University (2003)
Kyoto University (2000-2002)

Principal Investigator

市川 厚  武庫川女子大学, 薬学部, 教授 (10025695)

Co-Investigator(Kenkyū-buntansha) 田中 智之  京都大学, 薬学研究科, 助手 (40303846)
杉本 幸彦  京都大学, 薬学研究科, 助教授 (80243038)
扇間 昌親  武庫川女子大学, 薬学部, 教授 (90098533)
Project Period (FY) 2000 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥74,800,000 (Direct Cost: ¥74,800,000)
Fiscal Year 2003: ¥25,500,000 (Direct Cost: ¥25,500,000)
Fiscal Year 2002: ¥25,500,000 (Direct Cost: ¥25,500,000)
Fiscal Year 2001: ¥23,800,000 (Direct Cost: ¥23,800,000)
Keywordsマスト細胞(肥満細胞) / イムノグロブリンE / ヒスタミン / ヒスチジン脱炭酸酵素 / アレルギー / プロスタグランジン / カルシウム / 接着 / 細胞接着 / 分化 / アナフィラキシー / 骨髄培養 / イノムグロブリンE / アナフイラキシー
Research Abstract

本研究は炎症、アレルギー等の病態において重要な機能を有するマスト細胞の多様性に焦点をおき、個体レベルにおけるヒスタミンあるいはプロスタグランジン(PG)のはたらきを解明し、もって新規抗アレルギー薬創製に寄与する基礎的知見を得ることを目的としている。本年度の研究実施計画に基づき以下の知見を得た。
1.IgE感作によるマスト細胞活性化機構の解明
IL-3依存的な骨髄由来培養マスト細胞(BMMC)における単量体IgEによるCa^<2+>流入に関与するチャンネルは、抗原抗体反応の際に関与するものとは異なることを明らかにした。さらにIgEの抗原結合部位近傍の領域がIgE感作によるマスト細胞治性化に関与することを示唆する結果を得た。また、こうした単量体IgEの効果は腹腔マスト細胞では弱く、マスト細胞-線維芽細胞共培養系を用いた検討から細胞の分化に伴い応答性の減弱が起こることを見いだした。
2.HDC欠損マウス腹腔マスト細胞における顆粒形成の異常の解明
マウス腹腔からマスト細胞を精製し、GeneChip (Affymetrix)によるマイクロアレイ解析を行った。その結果、HDC欠損マウス腹腔マスト細胞における顆粒プロテアーゼ遺伝子群のmRNA発現の顕著な低下を見いだし、タンパク質レベルでもtryptase、carboxypeptidaseA、cathepsinGの発現が低下していることを明らかにした。
これらの結果から、慢性アレルギー状態においてIgE濃度が高まる際に、マスト細胞が油性化し、新規合成されるヒスタミンが顆粒酵素の誘導、あるいはマスト細胞の成熟を惹起することをはじめて示唆した。
3.PGE_2刺激によるマスト細胞の接着機構の解析
マウスマスト細胞株P-815ではPGE_2によるEP3、EP4両受容体を介する相乗的なcAMP産生を介して。フィブロネクチンへの細胞接着が誘導されることを見いだした。また、この作用には持続的なサイトゾルCa^<2+>レベルの亢進が関与しており、さらにカルモジュリン依存性たんばく質キナーゼ阻害剤W7により完全に阻害されることからCa^<2+>-カルモジュリンパスウェイが関与することを明らかにした。

Report

(4 results)
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • 2000 Annual Research Report
  • Research Products

    (26 results)

All Other

All Publications (26 results)

  • [Publications] Tanaka, S., Deai, K., Konomi, A., Takahashi, K., Yamane, H, Sugimoto, Y., Ichikawa, A.: "Expression of L-histidine decarboxylase in granules of elicited mouse polymorphonuclcar leukocytes"Eur.J.Immunol.. (In press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sugimolo, Y., Nakato, T., Kita, A., Takahashi, Y., Hatae, N., Tabata, H., Tanaka, S., Ichikawa, A.: "A cluster of aromatic amino acids in the i2 loop plays a key role for Gs coupling in prostaglandin EP2 and EP3 receptors."J.Biol.Chem.. 279. 11016-11026 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hatae, N., Kita, A., Sugimoto, Y., Ichikawa, A.: "Induction of adherent activity in mastocytoma P-815 cells by the cooperation of two PGE_2 receptor subtypes, EP_3 and EP_4."J.Biol.Chem.. 278. 17977-179981 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Tanaka, S., Deai, K., Inagaki, M., Ichikawa, A: "Uptake of histamine by mouse peritoneal macrophages and a macrophage ceil line, RAW264.7"Am.J.Physiol.-Cell Physiol.. 285. C592-C598 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Furutani, K., Aihara, T., Nukamura, E., Tanaka, S., Ichikawa, A., Ohtsu, H., Okabe, S.: "Crucial role of histamine for regulation of gastric acid secretion ascertained by histidine decarboxylase-knockout mice."J.Pharmacol.Exp.Ther.. 307. 331-338 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Oka, T., Oka, K., Kobayashi, T., Sugimoto, Y., Ichikawa, A., Ushikubi, F., Narumiya, S., Saper, CB.: "Characteristics of thermoregulatory and febrile responses in mice deficient in prostaglandin EP1 and EPS receptors."J.Physiol.. 551. 945-954 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hatae, N., Kita, A., Tanaka, S., Sugimoto, Y., Ichikawa, A.: "Induction of adherent activity in Mastocytoma P-815 cells by the Cooperation of Two PGE_2 receptor subtypes, EP3 and EP4"J.Biol.Chem.. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] Segi, E., et al.: "Expression of messenger RNA for prostaglandin E receptor subtypes EP4/EP2 and cyclooxygenase isozymes in mouse periovulatory follicles and oviducts during superovulation"Biol.Reprod.. 68. 804-811 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Takahashi, K., Tanaka, S., Furuta, K., Ichikawa, A.: "Histamine H_2 receptor-mediated modulation of local cytokine expression in a mouse experimental tumor model"Biochem.Biophys.Res.Commun.. 297. 1205-1210 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Tanaka, S., Takasu, Y., Mikura, S., Satoh, N., Ichikawa, A.: "Antigen-independent induction of histamine synthesis by immunoglobulin E in mouse bone marrow-derived mast cells"J.Exp.Med.. 196. 229-235 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hatae, N., Sugimoto, Y., Ichikawa, A.: "prostaglandin receptors : Advances in the study of EP3 receptors signaling"J.Biochem.. 131. 781-784 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yoshida, K., et al.: "Stimulation of bone formation and prevention of bone loss by prostaglandin E EP4 receptor activation"Proc.Natl.Acad.Sci. USA. 99. 4580-4585 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Safina.F., Tanaka S., Inagaki, M., Tsuboi, K., Sugimoto, Y., Ichikawa, A.: "Expression of L-histidine decarboxylase in mouse male germ cells"J. Biol. Chem.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kabashima.K, Saji.T, Murata.T, Nagamachi.M, Matsuoka.T, Segi.E, Sugimoto.Y, Kobayashi.T, Ichikawa.A, Narumiya.S: "Protective role of PGE receptor subtype-EP4 in intestinal inflammation"J. Clin. Invest.. (in press). (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanaka, S., Hamada, K., Sugita, Y., Tonai, S., Hunyady, B., Palkovits, M., Falus, A., Watanabe, T., Okabe, S., Ohtsu, H., Ichikawa, A., Nagy, A.: "Gastric acid secretion in L-histidine decarboxylase deficient mice"Gastroenterology. 122. 145-155 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hatae, N., Yamaoka, K., Sugimoto, Y., Negushi, M., Ichikawa, A.: "Augmentation of Receptor-Mediated Adenylyl Cyclase Activity by Gi-Coupled Prostaglandin Receptor Subtype EP3 in a Gβγ Subunit-Independent Manner"Biochem. Biophys. Res. Commun.. 290. 162-168 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ohtsu, H., Tanaka, S., Terui, T., Hori, Y., Makabe-Kobayashi, Y., Pejler, G., Tchougounova, E., Hellman, L., Gertsenoswin, M., Hirasawa, N., Sakurai, E., Buzas, E., Kovacs, P., Csal, G., Kittel, A., Okada, M., Hara, M., Mur, L., Numayama-Tsuruta, K., Ishigaki-Suzuki, S., Ohuchi, K., Ichikawa, A., Falus, A., Watanabe, T., Nagy, A.: "Mice lacking histidine decarboxylase exhibit abnormal mast cells"FEBS Lett.. 502. 53-56 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ma, H., Hara, A., Xiao, C-Y., Okada, Y., Takahata, O., Nakaya, K., Sugimoto, Y., Ichikawa, A., Narumiya, S., Ushikubi, F.: "Increased bleeding tendency and decreased susceptibility to thromboembolism in mice lacking the prostaglandin E receptor subtype EP3"Circulation. 104. 1176-1180 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tanaka, S., Hamada, K., Ohtsu, H., Watanabe, T., Falus, A., Nagy, A., Okabe, S., Ichikawa, A.: "Histamine Research in the New Millenium (Eds Watanabe, T., Timmerman, H., Yanai, K.)"Elsevier Science B. V.. 521 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ikegami,R., et al.: "The expression of prostaglandin E receptors EP2 and EP4 and their different regulation by LPS in C3H/HeN peritoneal macrophages."J.Immunol.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Takahashi,K., et al.: "Effect of cimetidine on intratumoral cytokine expression in an experimental tumor."Biochem.Biophys.Res.Commun.. (in press). (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Yamane,H., et al.: "Prostaglandin E2 receptor, EP2 and EP4, differentially modulate TNF-α and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils."Biochem.Biophys.Res.Commun.. 278. 224-228 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Matsuoka,T., et al.: "Prostaglandin D2 as a mediator of allergic asthma."Science. 287. 2013-2017 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Sugimoto,Y., et al.: "Distribution and function of prostanoid receptors : studies from knockout mice."Jpn.J.Pharmacol.. 83. 279-285 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tsuboi,K., et al.: "Uterine expression of prostaglandin H_2 synthase in late pregnancy and during parturition in prostaglandin F receptor-deficient mice."Endocrinology. 141. 315-324 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 田中智之 ほか: "ヒスタミン研究の最近の進歩(編集・渡邉 建彦)"医歯薬出版株式会社. 114 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2001-04-01   Modified: 2018-03-28  

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