Celecoxib 經由 phosphatidylionsitol 3-kinase 和 c-Jun-N-terminal kinase 訊息傳遞路徑誘導大鼠環間膜細胞血紅素氧化酵素-1的表現

Celecoxib induces heme oxygenase-1 expression via phosphatidylionsitol 3-kinase and c-Jun-N-terminal kinase dependent pathways in rat glomerular mesangial cells

洪淑麗(Shu-Li Hung)

指導教授 ： 李宏謨 博士

臺北醫學大學/醫學院/醫學檢驗生物技術學研究所/碩士(2004年)

摘要

Celecoxib 是一種非類固醇的抗發炎藥物，屬於selective COX-2 inhibitors的一種，藉由抑制cyclooxygenase-2 (COX-2) 進而抑制prostaglandin的合成。COX 的抑制劑所產生的副作用會造成腎臟受損。本篇研究論文將進一步了解其作用機制，發現celecoxib會刺激大鼠環間膜細胞表現HO-1這個壓力指標，在大鼠環間膜細胞中，隨著加入celecoxib的濃度及時間的增加，HO-1的表現也隨之增加。當加入自由基的淨化劑l-N-acetylcystein （L-NAC） 前處理後，發現會抑制celecoxib刺激大鼠環間膜細胞表現HO-1，同時也會抑制PI3-K及JNK訊息傳遞路徑的活化。Celecoxib 會藉由活化c-Jun-N-terminal kinase (JNK) 來誘導大鼠環間膜細胞表現HO-1，但不藉由ERK 44/42及 p38 MAPK訊息傳遞路徑。此外，當加入PI3-K的抑制劑 (LY 294002) 先處理，發現會抑制celecoxib刺激大鼠環間膜細胞表現HO-1、PDK-1及Akt/PKB 的磷酸化。因此本篇研究論文指出，celecoxib 會增加自由基的產生進而藉由 JNK及 PI3K的訊息傳遞路徑來誘導大鼠環間膜細胞表現HO-1。

關鍵字

大鼠環間膜細胞 ； 血紅素氧化酵素-1

並列摘要

Celecoxib is a cyclooxygenases-2 (COX-2) selective nonsteroidal anti-inflammatory drug (NSAIDs). A serious side effect of COX inhibitors is renal damage. To investigate the molecular basis of the renal injury, I evaluated the expression of the stress marker, heme oxygenase-1 (HO-1), in celecoxib-stimulated mesangial cells. Celecoxib induced dose- and time-dependent increases of HO-1 expression in glomerular mesangial cells. Pretreatmnet of mesangial cells with l-N-acetylcysteine, a free radical scavenger, suppressed celecoxib-induced HO-1 expression, suggesting reactive oxygen species (ROS) may play a role in this process. Indeed, incubation of glomerular mesangial cells with celecoxib increased ROS generation. Celecoxib-stimulated JNK kinase activity is inhibited by treatment with SP600125 (a specific JNK inhibitor). Consistently, celecoxib-induced HO-1 expression was attenuated by SP 600125, but not PD 98059 (a specific p42/44 MAPK inhibitor) or SB203580 (a specific p38 MAPK inhibitor). On the other hand, LY 294002, a phosphatidylinositol 3-kinase (PI3K)-specific inhibitor, inhibited celecoxib-induced HO-1 expression in cultured mesangial cells as demonstrated by inhibition of the phosphorylation of the PDK-1 and Akt/protein kinase B (PKB). In conclusion, these data suggest that celecoxib increases free radical generation, which triggers a signal transduction cascade involving JNK and PI3K signaling pathways, which in turn induces HO-1 expression in glomerular mesangial cells.

並列關鍵字

Celecoxib ； phosphatidylionsitol 3-kinase ； c-Jun-N-terminal kinase ； rat glomerular mesangial cells ； heme oxygenase-1

參考文獻

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