Research on transcription of mRNA of inducible NO synthase and supression of its degradation by proinflammatory cytokine.

诱导型 NO 合酶 mRNA 转录及促炎细胞因子抑制其降解的研究。

• 批准号: 11672172
• 负责人: HISAYAMA Tetsuhro
• 金额: $ 2.3万
• 依托单位: University of Tokushima
• 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-11672172/
• 关键词: vascular smooth muscle; TRAF6; enzyme induction; proinflammatory cytokine; interleukin 1; messenger RNA stability; p38 MAPkinase; inducible NO synthase; 一酸化窒素; 形質導入

In this research, we have carried out molecular cloning of TRAF6 involved in interleukin 1 (IL-1)-mediated expression of inducible nitric oxide synthase (iNOS), construction of its gene transfer system, and investigation on mechanisms of suppression of iNOS mRNA degradation via activation of IL-1 receptors. The transient expression of TRAF6 resulted in enhancement of the IL-1-induced iNOS mRNA production, while inhibited nuclear translocation of NF-kB by IL-1, suggesting a possibility that NF-kB could not necessarily mediate the IL-1-induced expression of the iNOS gene. Further, we for the first time, found that IL-1 suppressed a degradation of iNOS mRNA, and that p38 MAPkinase is involved in its signal transduction pathway. IL-1 selectively induced a double-phosphorylation of p38, but not on ERK or JNK, other subfamily of MAPkinases, and expression of a specific activator of p38, namely a constitutively activated variant of MKK6, suppressed a degradation of iNOS mRNA without application of IL-1. These results open a clue for development of new drugs and remedies against inflammatory diseases, and contribute to understanding of pathophysiological basis of proinflammatory cytokines.

本研究对白细胞介素1（IL-1）介导的诱导型一氧化氮合酶（iNOS）表达相关基因TRAF6进行了分子克隆，构建了TRAF6基因转移系统，并探讨了TRAF6通过激活IL-1受体抑制iNOS mRNA降解的机制。TRAF6的瞬时表达增强了IL-1诱导的iNOS mRNA的表达，但抑制了IL-1诱导的NF-κ B核转位，提示NF-κ B可能不一定介导IL-1诱导的iNOS基因表达。我们还首次发现IL-1可抑制iNOS mRNA的降解，并发现p38 MAPK激酶参与了其信号转导途径。IL-1选择性地诱导p38的双磷酸化，但不诱导ERK或JNK（MAP激酶的其它亚家族）的双磷酸化，并且p38的特异性激活剂（即MKK6的组成性激活变体）的表达在不应用IL-1的情况下抑制iNOSmRNA的降解。这些结果为开发抗炎性疾病的新药和治疗方法提供了线索，并有助于了解促炎细胞因子的病理生理基础。

项目成果

YOSHIZUMI,M.: "Effect of endothelin-1 (1-13) on human mesangial cell proliferation."Jpn.J.Pharmacol.. 84. 146-155 (2000)

YOSHIZUMI,M.：“内皮素-1 (1-13) 对人系膜细胞增殖的影响。”Jpn.J.Pharmacol.. 84. 146-155 (2000)