Epigal locatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production
Epigal locatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production
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DOI：
10.1073/pnas.0802675105
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发表时间：
2008-09-23
影响因子：
11.1
通讯作者：
Koch, Alisa E.
中科院分区：
文献类型：
--
作者：
Ahmed, Salahuddin;Marotte, Hubert;Koch, Alisa E.
通过施用可溶性gp 130（sgp 130）受体以捕获IL-6/可溶性IL-6 R复合物来调节IL-6信号转导已显示出治疗类风湿性关节炎（RA）的前景。然而，增强内源性sgp 130通过选择性剪接的gp 130基因尚未被测试。我们发现，表没食子儿茶素-3-没食子酸酯（EGCG），一种在绿色茶中发现的抗炎化合物，通过诱导gp 130 mRNA的选择性剪接，抑制IL-1 β诱导的RA滑膜成纤维细胞中IL-6的产生和信号转导，从而增强sgp 130的产生。使用大鼠泻药诱导的关节炎模型的体内研究结果显示，EGCG治疗大鼠的血清和关节中的IL-6水平分别特异性抑制28%和40%，同时改善大鼠泻药诱导的关节炎。我们还观察到一个显着减少膜结合的gp 130蛋白表达的EGCG治疗组的联合匀浆。相反，定量RT-PCR显示gp 130/IL-6 R α mRNA比率增加了约2倍，表明EGCG激活sgp 130的可能机制。明胶酶谱结果显示，EGCG抑制IL-6/可溶性IL-6 R诱导的RA滑膜成纤维细胞和关节匀浆中的基质金属蛋白酶-2活性，可能通过上调sgp 130合成。这些研究的结果提供了以前未描述的证据，IL-6的合成和transsignaling抑制EGCG与sgp 130上调的独特机制，从而持有作为RA的潜在治疗剂的希望。
Regulation of IL-6 transsignaling by the administration of soluble gp130 (sgp130) receptor to capture the IL-6/soluble IL-6R complex has shown promise for the treatment of rheumatoid arthritis (RA). However, enhancing endogenous sgp130 via alternative splicing of the gp130 gene has not yet been tested. We found that epigallocatechin-3-gallate (EGCG), an anti-inflammatory compound found in green tea, inhibits IL-1 beta-induced IL-6 production and transsignaling in RA synovial fibroblasts by inducing alternative splicing of gp130 mRNA, resulting in enhanced sgp130 production. Results from in vivo studies using a rat adjuvant-induced arthritis model showed specific inhibition of IL-6 levels in the serum and joints of EGCG-treated rats by 28% and 40%, respectively, with concomitant amelioration of rat adjuvant-induced arthritis. We also observed a marked decrease in membrane-bound gp130 protein expression in the joint homogenates of the EGCG-treated group. In contrast, quantitative RT-PCR showed that the gp130/IL-6R alpha mRNA ratio increased by similar to 2-fold, suggesting a possible mechanism of sgp130 activation by EGCG. Gelatin zymography results showed EGCG inhibits IL-6/soluble IL-6R-induced matrix metalloproteinase-2 activity in RA synovial fibroblasts and in joint homogenates, possibly via up-regulation of sgp130 synthesis. The results of these studies provide previously undescribed evidence of IL-6 synthesis and transsignaling inhibition by EGCG with a unique mechanism of sgp130 up-regulation, and thus hold promise as a potential therapeutic agent for RA.