臺灣博碩士論文加值系統

Bradykinin (BK)是一種內生性類胜肽，正常的生理功能中扮演調節血壓以及維持恆定的重要因子。許多研究文獻指出，BK為關節發炎反應中的介質進而導致骨質結構的破壞以及發炎反應的加劇。然而，vascular cell adhesion molecule-1 (VCAM-1)已被報導對於類風濕性關節炎的病人炎症反應上有很高的相關性。本篇論文中，針對人類類風濕性關節炎之滑液膜中纖維母細胞，探討 BK如何透過訊號傳遞的路徑調控VCAM-1的表現。利用RT-PCR以及西方墨點轉漬法分析，我們發現BK的確可以明顯誘導VCAM-1蛋白質和mRNA的表現，以及活化MAPKs (ERK1/2、JNK1/2以及p38)和transactivation路徑中Src、 EGFR、 Akt的磷酸化，而當我們前處理以上訊號傳遞的蛋白的抑制劑時，可以發現磷酸化的情形以及VCAM-1的表現都會受到抑制。因此推論BK會透過活化MAPKs and transactivation pathway誘導VCAM-1的表現，而MAPKs的活化作用亦會受到transactivation pathway的調控。另一方面在BK的作用之下，IkB-alpha 被促進分解，進而使活化態的NF-kB進入細胞中參與基因的調控，而這個過程也會受到MAPKs以及NF-kB抑制劑Bay11-7082所抑制，證實NF-kB進入細胞中參與基因的調控會受到MAPKs的調控作用。因此為了探討MAPKs在VCAM-1基因調控上扮演的重要性，我們利用promoter luciferasse assay以及免疫螢光的方式，發現MAPKs的確會明顯影響VCAM-1以及NF-kB promoter的活性和translocation。此外，我們還更進一步探討除了MAPKs之外，是否有其他訊號傳遞分子會參與這條路徑，我們使用了鈣離子BAPTA/EDTA以及PKC抑制劑Ro318220,、Rottlerin 以及Gö6976，發現的確會影響BK所誘導的VCAM-1表現。鈣離子的參與利用 Fura-2螢光偵測證實BK在RASFs中所誘導的VCAM-1表現會受到細胞內外鈣離子的共同調控。同時當細胞轉染(Transfection) dominant negative mutants or shRNA of MEK, ERK, p38, JNK, Src, p85, Akt 和PKC等，也分別抑制了BK所調控VCAM-1的表現。
BK引發VCAM-1的表現，也增加單核白血球(monocytes)在RASFs血管壁中的黏著，而這個情形也可以受到 HOE140、anti-VCAM-1、anti-ICAM-1、U0126、SB202190、SP600125、Bay11-7082、PP1、AG1296、AG1478、LY294002、BAPTA/EDTA、Ro318220、Rottlerin以及Gö6976所抑制。根據我們的實驗結果，BK誘導人類類風濕性關節炎之滑液膜中的纖維母細胞表現VCAM-1，是透過calcium、PKC、p42/p44 MAPK、p38 和JNK的磷酸化、receptor tyrosine kinase的轉活化(transactivation)和NF-kB、p300等訊號傳遞路徑調控。本篇論文對類風濕性關節炎中BK調控VCAM-1的表現機制有進一步的了解，更多關於BK和VCAM-1影響類風濕性關節炎病理過程的資訊，將有助於疾病的治療。

Many reports have shown that vascular cell adhesion molecules-1 (VCAM-1) plays an important role in joint disease and inflammation. In previous study, bradykinin (BK) has been shown to be a kind of inflammatory mediators in bone or brain inflammatory disease. However, the molecular mechanisms and physiological roles underlying BK-induced VCAM-1 expression in rheumatoid arthritis synovial fibroblasts remain unclear. Here, we reported that BK induced VCAM-1 protein and mRNA expression, via a B2 BK receptor-activated MAPKs, Src/EGFR, PI3K/Akt, Ca2+, protein kinase C and NF-kB signaling pathway. Transfection with dominant-negative plasmids or shRNA of MEK, ERK1/2, p38, JNK, Akt, NIK, IKK-alpha or IKK-beta also abolished the VCAM-1 expression induced by BK. Accordingly, BK-stimulated phosphorylation of p42/p44 MAPK, p38 MAPK, JNK, Src, EGFR and Akt was also attenuated by pretreatment with U0126, SB202190, SP600125, PP1, AG1478 and SH-5, respectively. Furthermore, activation of MAPKs led to promote translocation of p65 determined by immunofluorescence staining. MAPKs up-regulated VCAM-1 and NF-kB promoter activities were revealed by promoter assays. Previous study shows that VCAM-1 promoter has an AP-1 binding region. We reported that BK also induced c-jun and c-fos mRNA expression in RASFs. Finally, pretreatment with the inhibitors of PKC or Ca2+ chelator also attenuated BK-induced VCAM-1 protein and mRNA expression. Transfection with domainant negative plasmid of PKC-alpha or PKC-delta inhibited VCAM-1 expression induced by BK, suggesting that activation of PKC and increase of [Ca2+]i were essential for BK-induced VCAM-1 expression. BK-stimulated changes of [Ca2+]i was determined by using Fura-2/AM as an indicator. The data showed that BK stimulated Ca2+ release from internal stores and influx from external environment. Moreover, BK-stimulated monocytes adhering on synovial fibroblasts via VCAM-1 expression was decreased by pretreatment with inhibitors of MAPKs (U0126, SB202190, and SP600125), transactivation (PP1, AG1478, LY294002 and SH5) and Ca2+/PKC (BAPTA/EDTA, Ro318220, Rottlerin and Gö6976). Taken together, these results demonstrated that BK directly induces VCAM-1expression via B2 receptor, Ca2+, Src/EGFR, PI3K/Akt, MAPKs, transcription factor p65 and p300 pathway, which results in the promotion of cell adhesion on monocytes.

目 錄 (Contents)
誌謝......................................................3
縮寫表....................................................4
抑制劑表...................................................6
中文摘要 （Abstract in Chinese)............................7
英文摘要 （Abstract in English)............................8
緒論 （Introduction）......................................9
Specific aims............................................29
材料跟方法（Materials and Methods)........................30
實驗結果 （Results）......................................38
PART I:
Involvement of MAPKs and NF-kB in Bradykinin-induced VCAM-1 Expression in Rheumatoid Arthritis Synovial Fibroblasts..38
PART II:
Bradykinin-induced VCAM-1 Expression via Transactivation of Src/EGFR and PI3K/Akt in Human Rheumatoid Arthritis Synovial Fibroblasts.....................................50
PART III:
PKC and calcium involved in Bradykinin-induced expression vascular adhesion molecule-1 in Human Rheumatoid Arthritis Synovial Fibroblasts.....................................56
圖表 （Figures）..........................................60
討論 （Discussion）.......................................95
參考文獻 （References）...................................98

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