臺灣博碩士論文加值系統

在許多不同種類的細胞中，細胞激素(IL-1β)可以去誘導細胞基質金屬蛋白酶九型(MMP-9)的表現並且參與發炎反應。在本篇論文中，針對人類肺部表皮細胞(A549)來探討Mitogen-activated protein kinases (MAPKs)、Src、Receptor tyrosine kinases (RTKs)、 PI3K/Akt、Nuclear factor-κB (NF-κB)，以及Activator protein-1 (AP-1)，這些訊號傳遞路徑如何參與IL-1β誘導MMP-9的表現。在細胞先行處理MEK1/2抑制劑(U0126)、p38抑制劑(SB203580)、c-Jun N-terminal kinase (JNK)抑制劑(SP600125)之後，利用Gelatin Zymography, 西方點漬分析法以及Reverse transcriptase-polymerase chain reaction (RT-PCR)分析法，結果顯示IL-1β確實可以使p42/p44 MAPK、p38 MAPK，以及JNK磷酸化，並且這三種MAPKs的磷酸化反應分別也受到U0126、SB203580，以及SP600125的明顯抑制，進而抑制MMP-9的活性及表現。此外，MMP-9亦會受到Ras抑制劑(apigenin與manumycin A)、Raf抑制劑(GW5074)、Src抑制劑(PP1)、EGFR抑制劑(AG1478)、PDGFR抑制劑(AG1296)、PI3K抑制劑(LY294002與wortmannin)、NF-κB抑制劑(helenalin)，以及AP-1 抑制劑(curcumin)所抑制。為了更進一步確定PDGFR以及Src之間的關係，也使用共同免疫沉澱的方式來做探討。結果證明Src是PDGFR以及EGFR的一個上游蛋白，而Akt則是PDGFR以及EGFR的一個下游蛋白。再者，使用核、質分離以及免疫螢光染色，可確定受IL-1β刺激活化的NF-κB會轉位至核中，而IκBα則會分解。NF-κB的轉位作用，會被helenalin所抑制，SP600125會部分抑制，但U0126 及SB203580則不能。此外，包括p65，p300，乙醯化的histone H3，以及乙醯化的histone H4 都被發現參與了IL-1β誘發MMP-9 基因轉錄的核內機制。根據實驗結果可以推測IL-1β誘導人類肺部表皮細胞中MMP-9的表現是透過MAPKs的磷酸化，以及Src-EGFR/PDGFR-Akt的轉活化和NF-κB的轉位訊號傳遞調控途徑。這些實驗結果對於IL-1β誘導人類肺部表皮細胞基質金屬蛋白酶九型的表現和發炎的調控，除了增加了解兩者之間機轉上的關係，進而可以對於治療肺部的疾病有更多的幫助。

Interleukin-1β (IL-1β) has been shown to induce matrix metalloproteinase (MMP)-9 expression in various cell types and contribute to inflammatory responses. Here, we report that in lung epithelial cells (A549), the mitogen-activated protein kinases (MAPKs), Src, Receptor tyrosine kinases (RTKs), PI3K/Akt, and nuclear factor-κB (NF-κB) participate in MMP-9 expression induced by IL-1β. Zymographic, Western blotting, and RT-PCR analyses showed that IL-1β increased expression of MMP-9 mRNA and protein, which was inhibited by inhibitors of MEK1/2 (U0126), p38 (SB203580), and JNK (SP600125). IL-1β also stimulated phosphorylation of p42/p44, p38, and JNK which were attenuated by U0126, SB203580, and SP600125, respectively. In addition, IL-1β-induced MMP-9 protein expression in A549 were significantly attenuated by inhibitors of Ras (apigenin and manumycin), Raf (GW5074), Src (PP1), EGFR (AG1478), PDGFR (AG1296), PI3K (LY294002 and wortmannin), NF-κB (helenalin), and AP-1 (curcumin). Consistently, IL-1β-stimulated phosphorylation of Src, EGFR, PDGFR and Akt was attenuated by pretreatment with PP1, AG1478, AG1296, LY294002 and wortmannin, respectively. The sequential of Src and PDGFR phosphorylation stimulated by IL-1β was determined by co-immunoprecipitation. The results indicated that Src is the upstream component of PDGFR and EGFR, and then Akt is downstream component of PDGFR and EGFR in IL-1β-induced MMP-9 expression in A549. Moreover, IL-1β-stimulated translocation of NF-κB into the nucleus and degradation of IκBα was revealed by cell fraction isolation and immnofluorescence staining, which was blocked by helenalin and partially by SP600125 but not by U0126 and SB203580. The involvement of MAPKs in MMP-9 expresison was further confirmed by transfection with dominant negative mutants of MEK1/2, ERK1, p38, and JNK. Transfection with these mutants significantly inhibited IL-1β-induced MMP-9 expression. In addition, p65, p300, acetylated-histone H4 and H3 were involved in IL-1β-induced MMP-9 gene expression in the nucleus. Results obtained in this study provide more understanding of the regulatory mechanisms underlying IL-1β-induced MMP-9 expression mediated through MAPKs phosphorylation, transactivation of Src-EGFR/PDGFR-Akt, and NF-κB translocation in A549 cells. These results reveal more intact information of pathophysiological processes of pulmonary events, and prove beneficial in the therapeutic management of lung disease.

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碩士紙本論文著作授權書………………………………………………………………… iii
誌謝………………………………………………………………………………………… iv
中文摘要…………………………………………………………………………………… v
Abstract in English………………………………………………………………… vi
Abbreviations…………………………………………………………………………… vii
Inhibitors……………………………………………………………………………… ix
Content…………………………………………………………………………………… x
Introduction…………………………………………………………………………… 1
Appendix………………………………………………………………………………… 18
Materials and Methodes…………………………………………………………… 41
Cell culture of A549 cells……………………………………………………… 41
Western blot analysis……………………………………………………………… 42
MMP gelatin zymography…………………………………………………………… 43
Total RNA extraction and RT-PCR analysis………………………………… 43
NF-κB translocation………………………………………………………………… 45
Immunofluorescence staining…………………………………………………… 46
Co-immunoprecipitation…………………………………………………………… 46
Plasmids and transfection………………………………………………………… 47
Chromatin Immunoprecipitation assay………………………………………… 47
Results…………………………………………………………………………………… 50
Part I：IL-1β-induced MMP-9 expression is mediated by many signal compounds in A549 cells…………………………………………………………… 50
Part II：IL-1β-induced MMP-9 expression is mediated by NF-κB and regulated by p300 and histone……………………………………………………58
Figure legends………………………………………………………………………… 60
Discussion……………………………………………………………………………… 96
Conclusion……………………………………………………………………………… 102
References……………………………………………………………………………… 104

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