Functional roles of PI3 Kinase in immune system

PI3激酶在免疫系统中的功能作用

• 批准号: 13670322
• 负责人: SUZUKI Harumi
• 金额: $ 2.3万
• 依托单位: Yamaguchi University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670322/
• 关键词: PI3K; P85α; Btk; knockout mice; signal transduction; NF-kB; Akt; bcl-xL; PI3K; ノックアトマス; シグナルム伝達; マクロファージ; p85; 免疫

Mice deficient for p85α regulatory subunit of PI3-kinase showed impaired B cell development and activation, and their phenotype was nearly identical to that of Btk-/- mice. Since phosphatidylinositol-(3,4,5) triphosphate, a major product of PI3-kinases has been proposed to play a critical role in membrane recruitment and activation of Btk, phenotypic resemblance of these two knockout mice seemed to reveal direct functional association between PI3-K and Btk. However, BCR-induced activation of Btk in mouse B cells was unaffected by PI3K inhibitors or by the lack of phosphoinositide-3 kinase (PI3K). Consistent with this observation, PI3K/Btk double deficient mice show more severe defects than either single knockout mouse. Activation of NF-kB and induction of Bcl-x_L and cyclin D2 were severely blocked in both PI3K^<-/-> and Btk^<-/-> single deficient B cells and transgenic expression of Bcl-x_L restored the development and BCR-induced proliferation of B cells in PI3K^<-/-> mice. Our results collectively indicate that PI3K and Btk have unique roles in proximal BCR signaling, and they have a common target further downstream in the activation of NF-kB.

PI 3-激酶p85α调节亚基缺陷小鼠表现为B细胞发育和活化受损，其表型与Btk-/-小鼠几乎相同。由于磷脂酰肌醇-（3，4，5）三磷酸（PI 3-激酶的主要产物）在Btk的膜募集和激活中起关键作用，这两个基因敲除小鼠的表型相似性似乎揭示了PI 3-K和Btk之间的直接功能关联。然而，BCR诱导的小鼠B细胞中Btk活化不受PI 3 K抑制剂或缺乏磷酸肌醇-3激酶（PI 3 K）的影响。与该观察结果一致，PI 3 K/Btk双缺陷小鼠显示出比任一单敲除小鼠更严重的缺陷。在PI 3 K ^<-/->和Btk^<-/->单一缺陷B细胞中，NF-κ B的激活以及Bcl-x_L和细胞周期蛋白D2的诱导均被严重阻断，并且Bcl-x_L的转基因表达恢复了PI 3 K ^<-/->小鼠中B细胞的发育和BCR诱导的增殖。我们的研究结果共同表明，PI 3 K和Btk在近端BCR信号传导中具有独特的作用，并且它们在NF-kB的激活下游具有共同的靶点。

项目成果

Kozo Yasui, Yukio Sekiguchi, Motoki Ichikawa, Haruo Nagumo, Takashi Yamazaki, Atsushi Komiyama, Harumi Suzuki: "Granulocyte-macrophage colony stimulating factor delays neutrop hil apoptosis and primes its function through Ia-type phosphoin ositide 3-kinas

Kozo Yasui、Yukio Sekiguchi、Motoki Ichikawa、Haruo Nagumo、Takashi Yamazaki、Atsushi Komiyama、Harumi Suzuki：“粒细胞-巨噬细胞集落刺激因子可延迟中性粒细胞细胞凋亡，并通过 Ia 型磷酸肌苷 3-激酶启动其功能

Katsuyuki Tsunoda et al.: "Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris"Eur. J. Immunol.. 32. 627-633 (2002)

Katsuyuki Tsunoda 等人：“致病性自身抗体的产生需要实验性寻常型天疱疮的 T 细胞和 B 细胞中失去对桥粒芯糖蛋白 3 的耐受性”Eur。

Harumi Suzuki et al.: "PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction"Nature Immunol.. 4. 280-286 (2003)

Harumi Suzuki 等：“PI3K 和 Btk 差异调节 B 细胞抗原受体介导的信号转导”Nature Immunol.. 4. 280-286 (2003)

Koji Eshima et al.: "Lack of Evidence for Aggregation-Dependent Enhancement of p56lck in the Signal Transduction upon MHC Recognition by Mature T Cells"Immunology. 106. 46-52 (2002)

Koji Eshima 等人：“缺乏 p56lck 在成熟 T 细胞 MHC 识别信号转导中的聚集依赖性增强的证据”免疫学。

Harumi Suzuki, Satoshi Matsuda, Yasuo Terauchi, Mari Fujiwara, Toshiaki Ohteki, Tomoichiro Asano, Timothy W. Behrens, Taku Kouro, Kiyoshi Takatsu, Takashi Kadowaki, Shigeo Koyasu: "PI3K and Btk differentially regulate B cell antigen receptor-mediated sign

Harumi Suzuki、Satoshi Matsuda、Yasuo Terauchi、Mari Fujiwara、Toshiaki Ohteki、Tomoichiro Asano、Timothy W. Behrens、Taku Kouro、Kiyoshi Takatsu、Takashi Kadowaki、Shigeo Koyasu：“PI3K 和 Btk 差异调节 B 细胞抗原受体介导的信号