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

本研究对参与白细胞介素1（IL-1）介导的诱导型一氧化氮合酶（iNOS）表达的TRAF6进行了分子克隆，构建了其基因转移系统，并研究了通过激活IL-1受体抑制iNOS mRNA降解的机制。 TRAF6的瞬时表达导致IL-1诱导的iNOS mRNA产生增强，同时IL-1抑制NF-kB的核转位，这表明NF-kB不一定介导IL-1诱导的iNOS基因表达。此外，我们首次发现IL-1抑制iNOS mRNA的降解，并且p38 MAP激酶参与其信号转导途径。 IL-1选择性诱导p38的双磷酸化，但不诱导ERK或JNK（MAP激酶的其他亚家族）的双磷酸化，并且p38的特异性激活剂（即MKK6的组成型激活变体）的表达，在不应用IL-1的情况下抑制iNOS mRNA的降解。这些结果为开发抗炎性疾病的新药和疗法提供了线索，并有助于了解促炎细胞因子的病理生理学基础。

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.