雌性素和雌性素接受體在心肌細胞中透過抑制內毒素誘導細胞質內HuR以降低TLR4表現

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题名:	雌性素和雌性素接受體在心肌細胞中透過抑制內毒素誘導細胞質內HuR以降低TLR4表現 E2 and ERa reduce TLR4 expressions through inhibiting cytoplasmic translocation of HuR in LPS-treated H9c2 cardiomyoblast cells
作者:	黃碧玉;Pi-Yu Huang
贡献者:	醫學院基礎醫學研究所
关键词:	內毒素;LPS;TLR4;Hur;H9c2
日期:	2009
上传时间:	2010-09-29 12:13:51 (UTC+8)
摘要:	先前的研究發現：E2和ER?挶\|透過PI3K-Akt signaling pathway來抑制LPS所活化的JNK1/2，進而抑制I?羠降解與NF?羠進核、阻止LPS誘發TNF?悕Mactive caspase-3的表現與心肌細胞凋亡。TLR4 mRNA 在其3端之非轉譯區(3’untranslated regions; 3’UTR)通常含有AU-rich element(ARE)。ARE能與許多RNA結合蛋白(RNA-binding protein)作用調控mRNA穩定性。E2和ER?悁p何影響TLR4表現，並且LPS刺激心肌細胞是否會造成RNA結合蛋白表現上升並影響TLR4表現還未知。因此本實驗利用LPS刺激心肌細胞觀察RNA結合蛋白調控TLR4 mRNA表現和E2/ER?挬謅焆LR4的調控。由實驗結果得知，LPS透過磷酸化JNK顯著誘導TLR4 表現，增加細胞質中HuR的表現以加強TLR4 mRNA的穩定性。E2和ER?悗h會減少細胞質中HuR表現量並降低TLR4 mRNA穩定性，並減少TNF-?悕MIL-6在心肌細胞的表現。 Our previous results indicate that Akt mediates 17??-estradiol and/or estrogen receptor ?? to inhibit the LPS induced the JNK activity, TNF?? protein expression, and exhibit the cardioprotective effects. TLR4 mRNAs often contain AU-rich elements (AREs) in their 3’untranslated regions (3’UTR) which have a high affinity for RNA-binding proteins. It is not known whether E2 and ER?? affect the TLR4 mRNA stability and TLR4 protein expression through regulating the RNA-binding proteins, human antigen R (HuR), TTP and AUF-1 in myocardial cells. Therefore, we would like to investigate if the LPS induce these RNA-binding proteins to regulate TLR4 mRNAs of cardiomyocytes, and whether the E2/ER?? reduces the TLR4 mRNA stability induced by LPS through the inhibition of RNA-binding protein expression. Using doxycycline(Dox)-induced Tet-On ER?? H9c2 myocardic cell model, we want to identify whetherE2 and/or ER???nmanipulate the LPS-induced TLR4 mRNA stability. The result of western blotting and RT-PCR assays demonstrated that LPS significantly increased the level of cytoplasmic HuR protein and the stability of TLR4 mRNA, and farther induced the TLR4 protein expression in H9c2 cells. This effect was mediated through the phosphorylation of intracellular JNK. Interesting, E2 and ER?? decreased the cytoplasmic HuR level and TLR4 mRNA stability, and farther decreased the level of HuR protein and IL-6 proteins induced by LPS in H9c2 cardiomyoblast cells.
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