Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20102
標題: 腫瘤抑制基因HLJ1經由類鐸受體二之訊息傳遞路徑調控介白素八之表現
Tumor Suppressor HLJ1 Regulates Interleukin-8 Expression through Toll-like Receptor 2 Pathway
作者: 蔡銘珈
Tsai, Ming-Chia
關鍵字: heat shock protein;熱休克蛋白;toll like receptor;類鐸受體
出版社: 生物醫學研究所
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摘要: 
熱休克蛋白在很多的細胞中都會穩定表現,在細胞內扮演著很重要的角色。許多研究指出,熱休克蛋白不但參與了自發性的免疫系統,而且對於類鐸受體 (Toll-like receptors,TLRs) 訊號傳遞的路徑也有ㄧ定的影響,造成發炎反應的產生。在先前實驗室的研究發現,在非小細胞肺腺癌中過度表現熱休克蛋白,HLJ1 (Human Liver DnaJ-like protein),會使得介白素八 (interleukin-8,IL-8) 和類鐸受體受到影響,意味著HLJ1可能參與了類鐸受體與介白素的訊號傳遞路徑。因此,想進ㄧ步的探討是否HLJ1會透過類鐸受體的訊號傳遞而調控介白素8的表現。首先,共轉染 (co-transfection) HLJ1及TLR2或是TLR4到細胞中,藉由冷光報導基因分析觀察HLJ1對IL-8的調控。利用TLR2和TLR4及dominant-negative構築,包含:TLR4-mut, TLR2-Δ2, MyD88-DN和TRAF6-DN,進ㄧ步去釐清HLJ1經由哪條TLR路徑去調控IL-8的表現。再利用IL-8啟動子上不同轉錄因子結合區的突變,以冷光報導基因分析,確認HLJ1是經由哪個轉錄因子調控IL-8的表現,結果發現HLJ1主要是由AP1和NF-κB這兩個轉錄因子調控IL-8的表現。暫時性 (transiently) 的共轉染HLJ1和IL-8啟動子上不同突變位置的構築載體,由即時定量反轉錄聚合酶連鎖反應分析在mRNA層次上的變化,發現HLJ1會促進IL-8的表現。在暫時性共轉染HLJ1和TLR2時,更會使得IL-8的表現增加,但共轉染TLR4或TLR2-Δ2時,則沒有類似的情形。另外,在共轉染HLJ1和MyD88-DN或TRAF6-DN的情況下,HLJ1藉由TLR2所誘發的IL-8表現路徑受到阻斷,使HLJ1調控的IL-8表現無法大幅上升。這些結果顯示,HLJ1會經由TLR2-MyD88-TRAF6這條訊息傳遞路徑調控IL-8的表現。此外,從流式細胞技術中可以偵測到細胞表面上人類HLJ1重組蛋白的結合,由即時定量反轉錄聚合酶連鎖反應亦可以發現人類HLJ1重組蛋白會促進IL-8 mRNA的表現。若是先暫時性轉染TLR2後再以人類HLJ1重組蛋白處理細胞,經過冷光報導基因分析後發現IL-8的表現會因為TLR2的轉染,更提升了人類HLJ1重組蛋白對IL-8的調控,但在轉染TLR4或是TLR2-Δ2則沒有類似的情形發生。縱合上述的結果推測不論是人類HLJ1重組蛋白或是內生性的HLJ1主要都會經由TLR2-MyD88-TRAF6-AP1和TLR2-MyD88-TRAF6-NFκB這兩條訊息傳遞路徑來正調控IL-8的表現。

Heat shock proteins (HSPs) expressed constitutively in all cells are essential for several important cellular processes. As reported by several groups, HSPs are not only the potent activators of the innate immune system but also the mediators of the Toll-like receptors (TLRs) signaling pathways leading to proinflammatory responses. In our previous study, overexpression of HLJ1 (Human Liver DnaJ-like protein) in non-small cell lung carcinoma (NSCLC) cells indicated that HLJ1 might involve in the IL-8 regulation and TLRs signal pathways. Therefore, we are interested to know whether HLJ1 involves in the regulation of the TLRs signaling pathway to further regulate IL-8 expression. We first co-transfected HLJ1 with TLR2 or TLR4 constructs to evaluate IL-8 expression by luciferase reporter assay. The mutant and dominant-negative constructs, including TLR4-mut, TLR2-Δ2, MyD88-DN, and TRAF6-DN, were employed to clarify which TLR pathway is involved in IL-8 regulation. Further, the mutant constructs of IL-8 promoter were used to identify which cis-element of IL-8 promoter affected by HLJ1. The results of reporter gene assay further indicated that HLJ1 could regulate IL-8 expression via AP-1 and NFκB transcription factors. We also transiently co-transfected HLJ1 with above constructs to demonstrate IL-8 expression in RNA levels by real-time quantitative RT-PCR. By using real-time quantitative RT-PCR, we demonstrated that HLJ1 could up-regulate IL-8 expression. These results also showed that IL-8 expression was increased when co-transfecting HLJ1 with TLR2 constructs, but not with TLR4 or TLR2-Δ2. In addition, HLJ1 had no effect on regulating IL-8 expression when co-transfecting with MyD88-DN or TRAF6-DN. The results show that HLJ1 up-regulated IL-8 expression via TLR2-MyD88-TRAF6 signal pathway. Otherwise, the extra-recombinant HLJ1 could be observed on the cancer cell surface and up-regulated IL-8 expression by using flow cytometry and IL-8 real-time quantitative RT-PCR. The extra-recombinant HLJ1 could up-regulated IL-8 expression when transiently transfected TLR2 constructs, but not TLR4 or TLR2-Δ2 by using luciferase reporter assay. All of these results suggested that no matter endogenous HLJ1 or recombinant HLJ1 could up-regulate IL-8 expression through TLR2-MyD88-TRAF6-AP1 and TLR2-MyD88-TRAF6-NFκB signal pathways.
URI: http://hdl.handle.net/11455/20102
其他識別: U0005-2108200616195200
Appears in Collections:生物醫學研究所

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