死亡抵抗蛋白DRP对巨噬细胞TLR4信号转导的调控作用

发布时间：2018-12-23 10:35

【摘要】：本课题研究了死亡抵抗蛋白DRP对巨噬细胞TLR4信号转导的调控作用。主要包括在小鼠巨噬细胞RAW264.7中分别过表达和干扰DRP后,检测了相关细胞因子分泌的变化并对其机制做了初步探讨。实验结果表明,在巨噬细胞中过表达DRP后,抑制了LPS诱导的IL-6的产生但促进了IFN-β的产生,而DRP干扰后对LPS诱导的效应与此相反。其机制方面,DRP过表达后增强了LPS诱导的巨噬细胞中ERK和JNK的活化。相应地,干扰DRP后抑制了ERK和JNK的活化同时也抑制P38的活化。对于NF-κB途径,过表达DRP增强了IκB的磷酸化但抑制了NF-κB的转录活性。与此相吻合的是,干扰DRP后IκB的磷酸化程度降低但NF-κB的转录活性升高。此外,过表达DRP促进了LPS诱导的巨噬细胞IRF3磷酸化和Stat1的活化,相应的,干扰DRP后IRF3磷酸化程度降低,IRF3的入核减少,同时抑制了Stat1的活化。根据以上结果,我们认为DRP可以抑制TLR4的MyD88依赖通路的活化并且同时促进MyD88非依赖通路的活化,在TLR4的信号通路中可能作为两条通路的开关样(switch)分子,参与决定两条通路的活化方向。
[Abstract]:The aim of this study was to investigate the effects of death resistance protein (DRP) on TLR4 signal transduction in macrophages. After overexpression and interference with DRP in murine macrophages RAW264.7 the changes of cytokine secretion were detected and the mechanism was discussed. The results showed that the overexpression of DRP in macrophages inhibited the production of IL-6 induced by LPS but promoted the production of IFN- 尾, but the effect of DRP interference on LPS was opposite. In terms of its mechanism, overexpression of DRP enhanced the activation of ERK and JNK in macrophages induced by LPS. Accordingly, interference with DRP inhibited the activation of ERK and JNK as well as the activation of P38. For the NF- 魏 B pathway, overexpression of DRP enhances the phosphorylation of I 魏 B but inhibits the transcriptional activity of NF- 魏 B. In line with this, I 魏 B phosphorylation decreased but the transcriptional activity of NF- 魏 B increased after interfering with DRP. In addition, overexpression of DRP promoted IRF3 phosphorylation and Stat1 activation in macrophages induced by LPS. In response, IRF3 phosphorylation decreased and IRF3 nucleation decreased after interfering with DRP, and Stat1 activation was inhibited at the same time. Based on the above results, we suggest that DRP can inhibit the activation of TLR4's MyD88 dependent pathway and at the same time promote the activation of MyD88 independent pathway, which may act as a switch like (switch) molecule of two pathways in the signal pathway of TLR4. Participate in determining the activation direction of the two pathways.
【学位授予单位】：第二军医大学
【学位级别】：硕士
【学位授予年份】：2006
【分类号】：R392

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