1999 Fiscal Year Annual Research Report

アトピー原因遺伝子の同定とその機能解析に関する研究

Research Project

Project/Area Number	11148216
Research Institution	Kyushu University
Principal Investigator	出原賢治九州大学, 医学部, 助手 (00270463)
Co-Investigator(Kenkyū-buntansha)	柳原行義国立小児病院, 小児医療研究センター, 主任研究官 (00166547)
Keywords	アレルギー / インターロイキン13 / インターロイキン4 / 気管支喘息 / インターロイキン13レセプター / 一塩基多型 / 気道
Research Abstract	アレルギー疾患は遺伝因子と環境因子が組合わさって発症すると考えられている。本研究ではアレルギー疾患の遺伝子の候補遺伝子上の遺伝的多型の中から、アレルギー疾患の発症、病態形成に関与するものを同定し、その機能を解析することである。今回、我々は候補遺伝子としてIL-13遺伝子を選び出し、これとアレルギー発症との関連を解析した。まずIL-13遺伝子において、110番目のアミノ酸がアルギニンからグルタミンに置換される遺伝的多型を同定した。気管支喘息患者、正常者におけるこの遺伝的多型の出現頻度を解析したところ、日本人、イギリス人の両方でアトピー性、非アトピー性に関わらず喘息患者においてグルタミンの頻度が高くなっていた。この結果、IL-13遺伝子は喘息の原因遺伝子の一つであると考えられた。肺組織におけるIL-13の標的細胞を同定するために、抗IL-13Rα1モノクローナル抗体を作製し、免疫染色を行った。その結果、肺組織においては気道上皮細胞と気管支平滑筋にIL-13Rが高発現していた。これらの細胞におけるIL-13シグナル経路を解析するために、IL-13Rα1を細胞株に発現させて解析を行なった。その結果、IL-13Rα1が発現するとIL-4、IL-13刺激により転写因子であるSTAT3がSTAT6に加えて活性化されることが判明した。これらの事より、IL-13は気道上皮細胞、気管支平滑筋に直接作用して、STAT3、STAT6などを介して気管支喘息の発症に関わっていると考えられた。

Research Products

(16 results)

All Other

All Publications (16 results)

[Publications] Nobuko Kanai: "A "G" to "A" transition at the last nucleotide mutation of exon6 of the 8c gene(868G→A) may result in either a splice or missense mutation in patients with X-linked severe ****ed i**** defi*ien *y"Hum. Genet.. 104. 36-42 (1999)
[Publications] Hiromichi Mitsuyasu: "Dominant effect of Ile50ral variant of the human interleukin-4 receptor α chain in IgE synthesis"J. Immunol.. 162. 1227-1231 (1999)
[Publications] Yojiro Arinobu: "Antagonistic effect of an alternatice splice variant of IL-4, IL-4S2, on IL-4 activities in human monocytes and B cells"Cell. Immunol.. 191. 161-167 (1999)
[Publications] Kenji Izuhara: "Association of the interleukin-4 receptor α chain with p47phox, an antivator of the phagocyte NADPH oxidase in B cells"Mol. Immunol.. 36. 45-52 (1999)
[Publications] Mina Akaiwa: "Hakata antigen, a new member of the Ficolin/Opsonin p35 family, is a novel human lectin secreted into Bronchus/Alveolus and Bite"J. Histochem. Cytochem.. 47. 777-786 (1999)
[Publications] Kunihiro Yamaoka: "Selective DNA-binding activity of IL-IO-stimulated STAT moleules in human monocytes"J. Interferon Cytokine Res.. 19. 679-685 (1999)
[Publications] Kenji Izuhara: "The signal transduction via the interleukin-4 receptor and its correlation with atopy"Int. J. Mol. Med.. 3. 3-10 (1999)
[Publications] Kenji Izuhara: "Emerging therapectic targets in allergy : IL-4Rα and STAT6"Emerging therapectic targets. 3. 381-389 (19999)
[Publications] Taro Shirakawa: "Atopy and asthma : genetic variants of IL-4 and IL-13 signalling"Immunol. today. 21. 60-64 (2000)
[Publications] Masayuki Kojima: "Direct effect of lipopolysaccharide on prostaglandin E2 production by colon carcinoma through nuclear factor -kB activation and cyclooxygenase-2 induction"Oncogene. (in press).
[Publications] Kbws A. Heinzmann: "Genetic variants of IL-13 signalling and human asthma and atopy"Hum. Mol. Genet.. (in press).
[Publications] Akira Takabayashi: "Association between childhood atopic asthma and polymorphisms of three candidate genes : interleukin-4 receptor, interleukin-4 promoter and F** receptor genes"Exp. Clin. Immunogenet.. (in press).
[Publications] Pei-song Gao: "STAT6 and atopic asthma"J. Med. Genet.. (in press).
[Publications] Kenji Izuhara: "Recent advences in understanding how interleukin-13 signals are involved in the pathogenesis of bronchial asthma"Arch. Immunol. Therap.. (in press).
[Publications] Kenji Izuhara: "Atopy and the human interleukin-4 receptor α chain"J. Allergy Clin. Immunol.. (in press).
[Publications] 出原賢治: "IgE-FcεRI-マスト細胞枢軸とサイトカイン(アトピー素因とアレルギー炎症に関与するサイトカイン)"ファーマインターナショナル. 171 (1999)

1999 Fiscal Year Annual Research Report

アトピー原因遺伝子の同定とその機能解析に関する研究

Principal Investigator

出原 賢治 九州大学, 医学部, 助手 (00270463)

Research Products

[Publications] Nobuko Kanai: "A "G" to "A" transition at the last nucleotide mutation of exon6 of the 8c gene(868G→A) may result in either a splice or missense mutation in patients with X-linked severe ****ed i**** defi*ien *y"Hum. Genet.. 104. 36-42 (1999)

[Publications] Hiromichi Mitsuyasu: "Dominant effect of Ile50ral variant of the human interleukin-4 receptor α chain in IgE synthesis"J. Immunol.. 162. 1227-1231 (1999)

[Publications] Yojiro Arinobu: "Antagonistic effect of an alternatice splice variant of IL-4, IL-4S2, on IL-4 activities in human monocytes and B cells"Cell. Immunol.. 191. 161-167 (1999)

[Publications] Kenji Izuhara: "Association of the interleukin-4 receptor α chain with p47phox, an antivator of the phagocyte NADPH oxidase in B cells"Mol. Immunol.. 36. 45-52 (1999)

[Publications] Mina Akaiwa: "Hakata antigen, a new member of the Ficolin/Opsonin p35 family, is a novel human lectin secreted into Bronchus/Alveolus and Bite"J. Histochem. Cytochem.. 47. 777-786 (1999)

[Publications] Kunihiro Yamaoka: "Selective DNA-binding activity of IL-IO-stimulated STAT moleules in human monocytes"J. Interferon Cytokine Res.. 19. 679-685 (1999)

[Publications] Kenji Izuhara: "The signal transduction via the interleukin-4 receptor and its correlation with atopy"Int. J. Mol. Med.. 3. 3-10 (1999)

[Publications] Kenji Izuhara: "Emerging therapectic targets in allergy : IL-4Rα and STAT6"Emerging therapectic targets. 3. 381-389 (19999)

[Publications] Taro Shirakawa: "Atopy and asthma : genetic variants of IL-4 and IL-13 signalling"Immunol. today. 21. 60-64 (2000)

[Publications] Masayuki Kojima: "Direct effect of lipopolysaccharide on prostaglandin E2 production by colon carcinoma through nuclear factor -kB activation and cyclooxygenase-2 induction"Oncogene. (in press).

[Publications] Kbws A. Heinzmann: "Genetic variants of IL-13 signalling and human asthma and atopy"Hum. Mol. Genet.. (in press).

[Publications] Akira Takabayashi: "Association between childhood atopic asthma and polymorphisms of three candidate genes : interleukin-4 receptor, interleukin-4 promoter and F** receptor genes"Exp. Clin. Immunogenet.. (in press).

[Publications] Pei-song Gao: "STAT6 and atopic asthma"J. Med. Genet.. (in press).

[Publications] Kenji Izuhara: "Recent advences in understanding how interleukin-13 signals are involved in the pathogenesis of bronchial asthma"Arch. Immunol. Therap.. (in press).

[Publications] Kenji Izuhara: "Atopy and the human interleukin-4 receptor α chain"J. Allergy Clin. Immunol.. (in press).

[Publications] 出原賢治: "IgE-FcεRI-マスト細胞枢軸とサイトカイン(アトピー素因とアレルギー炎症に関与するサイトカイン)"ファーマインターナショナル. 171 (1999)

出原賢治九州大学, 医学部, 助手 (00270463)

[Publications] Nobuko Kanai: "A "G" to "A" transition at the last nucleotide mutation of exon6 of the 8c gene(868G→A) may result in either a splice or missense mutation in patients with X-linked severe ed i defiien y"Hum. Genet.. 104. 36-42 (1999)