【摘要】：本課題研究了死亡抵抗蛋白DRP對巨噬細胞TLR4信號轉(zhuǎn)導的調(diào)控作用。主要包括在小鼠巨噬細胞RAW264.7中分別過表達和干擾DRP后,檢測了相關細胞因子分泌的變化并對其機制做了初步探討。實驗結果表明,在巨噬細胞中過表達DRP后,抑制了LPS誘導的IL-6的產(chǎn)生但促進了IFN-β的產(chǎn)生,而DRP干擾后對LPS誘導的效應與此相反。其機制方面,DRP過表達后增強了LPS誘導的巨噬細胞中ERK和JNK的活化。相應地,干擾DRP后抑制了ERK和JNK的活化同時也抑制P38的活化。對于NF-κB途徑,過表達DRP增強了IκB的磷酸化但抑制了NF-κB的轉(zhuǎn)錄活性。與此相吻合的是,干擾DRP后IκB的磷酸化程度降低但NF-κB的轉(zhuǎn)錄活性升高。此外,過表達DRP促進了LPS誘導的巨噬細胞IRF3磷酸化和Stat1的活化,相應的,干擾DRP后IRF3磷酸化程度降低,IRF3的入核減少,同時抑制了Stat1的活化。根據(jù)以上結果,我們認為DRP可以抑制TLR4的MyD88依賴通路的活化并且同時促進MyD88非依賴通路的活化,在TLR4的信號通路中可能作為兩條通路的開關樣(switch)分子,參與決定兩條通路的活化方向。
[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.
【學位授予單位】：第二軍醫(yī)大學
【學位級別】：碩士
【學位授予年份】：2006
【分類號】：R392

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