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研究生:曾珮娸
研究生(外文):Pei-Chi Tseng
論文名稱:Helioxanthin在人類肝癌細胞中抗發炎活性之機制探討
論文名稱(外文):Mechanistic Studies of Anti-inflammatory Activity of Helioxanthin in Human Hepatoma Cells
指導教授:葉小帆葉小帆引用關係
指導教授(外文):Sheau-Farn Yeh
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生化暨分子生物研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:121
中文關鍵詞:介白素-1趨化因子抗發炎
外文關鍵詞:IL-1betachemokineHE-145anti-inflammatory
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介白素-1β (IL-1β) 過度活化趨化因子 (CC-chemokines) 的表現和慢性肝炎疾病及肝癌有密不可切的關係,因此,利用IL-1β於人類肝癌細胞株中可活化 CC-chemokines 表現之現象,以在細胞系統中篩選出對肝臟細胞有抗發炎活性的天然化合物。在初步的實驗中發現,一具有抗B型肝炎病毒 (HBV) 活性的天然木酚素 Helioxanthin (HE-145) 可以有效地在肝癌細胞株中抑制 IL-1β 所活化的趨化因子 MIP-1β 及 RANTES 之表現量。本論文將研究 IL-1β 對於活化 MIP-1β 及 RANTES 基因表現之調控機制,此外,因HE-145具有發展為治療慢性肝炎藥物的潛力,所以也將深入探討HE-145抑制發炎相關基因的轉錄因子 c-jun 和 NF-κB 之作用機制。
為了解 HE-145 於肝癌細胞 Huh7 中抑制 IL-1β 所活化的 MIP-1β 表現之作用機制,我們先分析 IL-1β 調控 MIP-1β 的分子機制。首先,透過不同的 MAPK 抑制劑,發現 JNK 以及 p38 MAPK 分別以不同的抑制程度參與 IL-1β 活化 MIP-1β 表現時的訊息調控。HE-145 能專一性地抑制 IL-1β 所活化的 c-jun 蛋白質表現及其磷酸化的程度,同時不影響 IL-1β 所活化的 JNK。此外,HE-145 對 IL-1β 所活化的p38、CREB1 和 ATF2 並沒有抑制作用,但是細胞在經過 HE-145 的處理後,會降低細胞中 CREB1 蛋白表現量。在點突變分析及電泳遷移率變動分析 (EMSA) 的實驗中顯示, IL-1β 會促進 c-jun 和 CREB1 所形成的異體二具體 (heterodimer) 於 MIP-1β 啟動子上結合到主要調控的 AP-1/CRE 序列。HE-145 對 IL-1β 活化 MIP-1β 啟動子活性的抑制作用會因過量表現轉錄因子 c-jun 而完全回復 MIP-1β 啟動子的活性;EMSA 和染色質免疫沉澱 (ChIP) 實驗同時證明了在細胞中 HE-145 會降低 c-jun 和 CREB1 結合到 AP-1/CRE 序列的能力。以上結果建立了 c-jun 在 IL-1β 活化 MIP-1β 表現中扮演的重要角色,且 CREB1 在其中似乎也有部分的貢獻。因此,HE-145 對於抑制 IL-1β 活化 MIP-1β 表現的作用主要是藉由降低 IL-1β 活化 c-jun 表現及 c-jun/CREB1 異體二具體結合至 AP-1/CRE 調控序列的量所導致。
HE-145 抑制 c-jun 的作用機轉也進一步的被釐清。當細胞經過 HE-145 的短時間處理後即能抑制原本內生性和 IL-1β 所活化的 c-JUN 信息核醣核酸和其蛋白質表現,但其並未影響到 IL-1β 活化 c-jun 磷酸化的層面;同時,c-jun 所主導的 AP-1 序列結合活性也理所當然的受到HE-145的抑制。另一方面,HE-145 是直接在基因轉錄層次上抑制 c-JUN 的信息核醣核酸表現,並非透過影響 c-JUN 信息核醣核酸和蛋白質的穩定度,且不需要任何新合成蛋白質的輔助。利用 EMSA 和 ChIP 實驗,可證明 HE-145 會直接作用在 c-jun 蛋白質上,並干擾 c-jun 對其本身啟動子上 AP-1 調控序列的結合活性,進而造成抑制 c-JUN 基因轉錄。
除了 AP-1 之外,NF-κB 也是掌控發炎基因的主要轉錄因子,近年來也變成抗發炎藥物開發的熱門標的物。RANTES 是已知受 NF-κB 調控的基因,實驗發現 HE-145 可以抑制 IL-1β 活化人類肝癌細胞 Hep3B 中的 RANTES 表現。首先,已證實 NF-κB 在 IL-1β 活化 RANTES 表現中的調控角色,並定義出 RANTES 啟動子上重要的調控序列 κB1。在分析 HE-145 對 NF-κB 的作用中,發現 HE-145 可抑制 IL-1β 活化 NF-κB 報導基因的活性,但是 IL-1β 活化的 NF-κB 進核步驟並不受 HE-145 影響;雖然如此,HE-145 仍能抑制 NF-κB 和其相對應的序列結合能力並且降低 p65 的轉錄活性。因此,即使在過量表現 p65 的情形之下,HE-145 仍能抑制 NF-κB 報導基因活性和 RANTES 基因表現。
本論文證明了 HE-145 在肝癌細胞中新穎的抗發炎活性,並探討其作用機制是來自於 HE-145 能干擾 AP-1 和 NF-κB 轉錄因子的結合能力及轉錄活性。HE-145 對於抗 HBV 和抗發炎所展現的雙重活性,開啟了將 HE-145 發展成治療 HBV 引起的慢性肝炎疾病及預防肝癌形成之藥物的新契機。
Elevated levels of CC-chemokines induced by interleukin-1β (IL-1β) have been correlated with chronic hepatic inflammatory diseases and hepatocellular carcinoma (HCC) formation. HE-145, a natural lignan with a unique anti-HBV activity, was shown to inhibit IL-1β-induced MIP-1β and RANTES production in Huh7 and Hep3B cells respectively. In the current work, the molecular mechanism of inhibitory activities of HE-145 on both the IL-1β-induced MIP-1β and RANTES expression and the inflammatory transcription factors c-jun and NF-κB will be elucidated.
HE-145 inhibited IL-1β-induced MIP-1β expression in a dose-dependent manner in Huh7 cells. To understand the mode action of HE-145, IL-1β-induced MIP-1β expression at the molecular level was examined. Using selective inhibitors, JNK and p38 pathways were found to participate in IL-1β-induced MIP-1β expression. HE-145 specifically suppressed IL-1β-induced c-jun protein expression and phosphorylation without affecting IL-1β-induced JNK activation. On the other hand, HE-145 had no effect on IL-1β-induced phosphorylation of p38, CREB1 or ATF2 although CREB1 protein expression was suppressed by HE-145. Mutational analysis and supershift assays indicated that IL-1β stimulated c-jun/CREB1 heterodimer binding to the essential AP-1/CRE site of the MIP-1β promoter. However, EMSA and ChIP assays consistently revealed that HE-145 reduced c-jun and CREB1 binding to the AP-1/CRE site in vivo. The inhibitory effect of HE-145 on IL-1β-induced MIP-1β promoter activity was completely reversed by overexpressing c-jun but not CREB1. Overall, these results established a major role of c-jun in IL-1β-induced MIP-1β expression in hepatoma cells, whereas CREB1 appeared to play a minor role in that. As a result, the specific reduction in IL-1β-induced c-jun expression and subsequent binding of the c-jun/CREB1 heterodimer to AP-1/CRE site contributed to the inhibitory action of HE-145 on IL-1β-induced MIP-1β production.
HE-145 rapidly inhibited both the basal and IL-1β-induced c-JUN mRNA and protein expression but not IL-1β-induced c-jun phosphorylation level. Meanwhile, c-jun-mediated AP-1 DNA-binding activity was suppressed by HE-145. Besides, HE-145 down-regulated c-JUN mRNA expression directly at transcriptional level independent of de novo protein synthesis, while HE-145 did not affect the stabilities of c-JUN mRNA and protein. Using EMSA and ChIP assays, HE-145 has been found to inhibit c-JUN transcription via directly interfering with c-jun binding to the regulatory AP-1 elements of the human c-JUN promoter region.
In addition to AP-1, nuclear factor-κB (NF-κB) is a central mediator of inflammation and potential anti-inflammatory target which regulates numerous inflammatory genes expression. RANTES, one of the IL-1β-induced NF-κB-dependent genes, was suppressed at mRNA and protein level in response to HE-145 pretreatment in Hep3B cells. The central role of NF-κB and the κB1 site (-53 to -44) in IL-1β-induced RANTES expression was further substantiated, in which HE-145 acted as a novel NF-κB inhibitor. HE-145 inhibited IL-1β-induced NF-κB reporter gene activity and impaired DNA-binding activity and transactivation activity of NF-κB without preventing IL-1β-induced nuclear translocation of NF-κB. In consequence, HE-145 was shown to suppress NF-κB reporter activity and RANTES gene expression in the presence of ectopically over-expressed p65.
In summary, this thesis presented a natural product HE-145 with a novel anti-inflammatory activity in hepatoma cells and clearly demonstrated its ability of inhibiting IL-1β-induced MIP-1β and RANTES expression through directly interfering with the transcription machineries of AP-1 and NF-κB complex. The dual biological activities of HE-145 in human hepatoma cells, namely the inhibition of HBV replication and anti-inflammation, promised HE-145 to be developed into a therapeutic agent for HBV-induced hepatic inflammatory diseases and preventing concomitant HCC formation.
中文摘要……………………………………………………………..2
Abstract……………………………………………………………..4
Abbreviations……………………………………………………….6
Introduction…………………………………………………………7
1. Physiological and pathological roles of inflammation……………………………………7
2. Key mediators linking inflammation and cancer…………………………………………9
3. Signal pathways activated by IL-1β..17
4. Anti-inflammatory therapies and drug...................................20
5. A natural lignan: Helioxanthin (HE-145)………………………………………………….21
Specific Aims…………………………………………………23
Materials and Methods…………………………………….24
Results……………………………………………………..37
1. Suppressive effect of HE-145 on IL-1β-induced MIP-1β gene expression……………….37
2. Molecular mechanism of the suppressive effect of HE-145 on c-jun expression……..…..41
3. Suppressive effect of HE-145 on NF-κB and the responsive gene RANTES……………..46
Discussion……………………………………………………50
1. Suppressive effect of HE-145 on IL-1β-induced CC-chemokines expression……………50
2. Molecular mechanism of the inhibitory action of HE-145 on c-jun……………………....56
3. Conclusion and perspective..………………………59
References……………………………………………………61
Figures………………………………………………………70
Appendices……………………………………………………112
Publication
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