茶鹼衍生物在大鼠氣管平滑肌細胞對抗腫瘤壞死因子誘發有關發炎之細胞內訊息傳遞

Xanthine derivatives inhibit TNF-α-induced inflammatory signaling in rat tracheal smooth muscle cells.

陳建文(Chien-Wen Chen)

指導教授 ： 陳英俊

高雄醫學大學/醫學院/醫學研究所/碩士(2004年)

摘要

和發炎有關的細胞激素TNF-α會減少大鼠氣管平滑肌細胞裡cGMP的量，以及減少sGCα1、sGCβ1和 PKG的蛋白質表現。另外，TNF-α會增加iNOS的表現，進而增加NO的生成。當前處理aminoguanidine（iNOS的抑制劑）來抑制NO的大量生成時，則可以避免TNF-α減少sGCα1、sGCβ1和 PKG的蛋白質表現；顯示TNF-α能減少sGCα1、sGCβ1和 PKG的蛋白質表現和NO有相關性。8-Br-cGMP是一個cGMP的類似物，它可以避免TNF-α增加iNOS的表現和NO的生成，並且可以使減少的sGCα1、sGCβ1和 PKG蛋白質表現回復到正常。一些能增加cGMP的試劑，例如theophylline、zaprinast、KMUP-1和KMUP-3，也都能和8-Br-cGMP一樣，產生相同的效果。這些結果顯示KMUP-1和KMUP-3具有cGMP調節的抗發炎作用。
除此之外，TNF-α會增加大鼠氣管平滑肌細胞的COX-2表現、PGE2和 6-keto-PGF1α (PGI2代謝後的產物)的生成、cAMP的量以及PKA的表現。因為dexamethasone（非選擇性的COX-2抑制劑）和NS-398（選擇性的COX-2抑制劑）都能抑制TNF-α引起的PKA表現，所以這可能顯示TNF-α能增加PKA的表現是因為氣管平滑肌細胞受TNF-α的刺激後產生的這些PGE2和PGI2。另外，當前處理KMUP-1和KMUP-3時，並不能有效的影響TNF-α引起的COX-2的表現以及PGE2和PGI2的生成。而isoproterenol、theophylline、KMUP-1和KMUP-3都能增加氣管平滑肌的cAMP，但是當有TNF-α的存在時，他們並不能有效的影響cAMP的生成。

關鍵字

茶鹼衍生物 ； 大鼠氣管平滑肌細胞 ； 腫瘤壞死因子.發炎 ； 細胞激素

並列摘要

Exposure of rat tracheal smooth muscle cells (TSMCs) to pro-inflammatory cytokine TNF-α decreased expressions of sGCα1, sGCβ1, PKG and production of cGMP. In addition, TNF-αincreased iNOS expression and NO production in TSMCs. Pretreatment of TSMCs with aminoguanidine (selective iNOS inhibitor) prevented TNF-α-mediated decrease in sGCα1, sGCβ1 and PKG expressions, indicated that TNF-α decreased sGCα1, sGCβ1 and PKG expressions in a NO-dependent mechanism. 8-Br-cGMP, a cGMP analog, prevented TNF-α-induced increase of iNOS protein and NO levels, and reversed the decrease of sGCα1, sGCβ1 and PKG expressions. cGMP-enhancing agents, such as theophylline, zaprinast, KMUP-1 and KMUP-3, all prevented the above effects of TNF-α in TSMCs. These results indicate that KMUP-1 and KMUP-3 have a cGMP-mediated anti-inflammatory property in TSMCs.
In addition, TNF-α increased COX-2 expression, PGE2 and 6-keto-PGF1α (PGI2 stable metabolite) production, cAMP levels and PKA expression. It is like that the increase in PKA expression induced by TNF-α is the result of increased PGE2 and PGI2 formation by TSMCs. Both dexamethasone (nonselective COX-2 inhibitor) and NS-398 (nonselective COX-2 inhibitor) prevented TNF-α-induced increase in PKA expression. Pretreatment of TSMCs with KMUP-1 and KMUP-3 had no significant effect on TNF-α-induced COX-2 expression, PGE2 and 6-keto-PGF1α (PGI2 stable metabolite) production. Isoproterenol, theophylline, KMUP-1 and KMUP-3 caused an increase in cAMP production but they had no significant effects in the presence of TNF-α.

並列關鍵字

Xanthine derivatives ； TNF-α ； inflammatory ； rat tracheal smooth muscle cells ； cytokine

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