Analysis of in vivo role of STAT3

STAT3体内作用分析

• 批准号: 11670149
• 负责人: TAKEDA Kiyoshi
• 金额: $ 2.3万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-11670149/
• 关键词: STAT3; knockout mice; macrophage; chronic colitis; IL-10; conditional gene targeting; 皮膚; 乳腺

STAT family proteins are involved in cytokine signaling pathways. I analyzed in vivo roles of STAT3. STAT3-deficient mice are early embryonic lethal. Therefore, to assess the role of STAT3 in cytokine-mediated biologic functions, we deleted STAT3 in a tissue-specific manner using Cre-loxP recombination system. First, we deleted STAT3 in T cells. STAT3-deficient T cells showed the enhanced apoptosis due to lack of IL-6-induced prevention of apoptosis. When we deleted STAT3 in macrophages, these mutant mice developed chronic enterocolitis. STAT3-deficient macrophages are abnormally activated due to lack of IL-10-mediated suppression of macrophage activity. In addition to the immune system, we deleted STAT3 in mammary gland and skin. In mammary gland, STAT3 has been demonstrated to be important for induction of apoptosis of epithelial cells after weaning. In skin, STAT3 has been shown to be important for wound healing mediated by enhancement of keratinocyte motility induced by growth factors.Thus, tissue-specific targeting of STAT3 revealed its important roles in various aspects of biological functions.

STAT家族蛋白参与细胞因子信号转导通路。我分析了STAT3在体内的作用。STAT3基因缺陷的小鼠是早期胚胎致死的。因此，为了评估STAT3在细胞因子介导的生物功能中的作用，我们使用Cre-loxP重组系统以组织特异性的方式删除了STAT3。首先，我们删除了T细胞中的STAT3。STAT3基因缺失的T细胞由于缺乏IL-6诱导的细胞凋亡抑制作用而表现出明显的凋亡增强。当我们删除巨噬细胞中的STAT3时，这些突变的小鼠患上了慢性小肠结肠炎。由于缺乏IL-10介导的巨噬细胞活性抑制，STAT3缺陷的巨噬细胞被异常激活。除了免疫系统，我们还删除了乳腺和皮肤中的STAT3。在乳腺中，STAT3已被证明在诱导断奶后的上皮细胞凋亡中起重要作用。在皮肤中，STAT3被证明是通过促进生长因子诱导的角质形成细胞的运动而在伤口愈合中起重要作用的，因此，组织特异性靶向STAT3揭示了它在生物功能的各个方面的重要作用。

项目成果

Takeda,k.: "STAT family of transcription factors in cytokine-mediated biological responses."Cytokine Growth Factor Rev.. 11. 199-207 (2000)

Takeda,k.：“细胞因子介导的生物反应中转录因子的 STAT 家族。”细胞因子生长因子 Rev.. 11. 199-207 (2000)

Hoshino, K.: "Absence of IL-1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function."J.Exp.Med.. 190. 1541-1548 (1999)

Hoshino, K.：“IL-1 受体相关 T1/ST2 的缺失不会影响 2 型辅助 T 细胞的发育及其效应功能。”J.Exp.Med.. 190. 1541-1548 (1999)

Kawai, T.: "Unresponsiveness of MyD88-deficient mice to endotoxin."Immunity. 11. 115-122 (1999)

Kawai, T.：“MyD88 缺陷小鼠对内毒素无反应。”免疫。

Sano,S.: "Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis."EMBO J.. 18. 4657-4668 (1999)

Sano,S.：“Stat3 的角质形成细胞特异性消融表现出皮肤重塑受损，但不影响皮肤形态发生。”EMBO J.. 18. 4657-4668 (1999)

Hashimoto, A.: "Essential role of phospholipase C-γ2 in B cell development and function."J.Immunol.. 165. 1738-1742 (2000)

Hashimoto, A.：“磷脂酶 C-γ2 在 B 细胞发育和功能中的重要作用。J.Immunol.. 165. 1738-1742 (2000)