Suppression of prostaglandin E2-induced MUC5AC overproduction by RGS4 in the airway
Suppression of prostaglandin E2-induced MUC5AC overproduction by RGS4 in the airway
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DOI：
10.1152/ajplung.90396.2008
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发表时间：
2009-04-01
影响因子：
4.9
通讯作者：
Yoon, Joo-Heon
中科院分区：
文献类型：
--
作者：
Song, Kyoung Seob;Choi, Yeon Ho;Yoon, Joo-Heon
Song KS，Choi YH，Kim JM，Lee H，Lee TJ，Yoon JH.气道中RGS 4对前列腺素E-2诱导的MUC 5AC过度产生的抑制。美国生理学杂志肺细胞分子生理学296：L 684-L 692，2009年。首次发表于2009年2月6日; doi：10.1152/ajplung.90396.2008。前列腺素E（EP）受体参与PGE（2）诱导的气道粘蛋白5AC（MUC 5AC）基因表达的机制尚不清楚。此外，关于影响PGE（2）诱导的MUC 5AC过量产生的负调控机制和/或蛋白质的报道很少。在本研究中，我们发现PGE（2）以剂量依赖性方式诱导MUC 5AC基因表达（EC 50：73.31 +/- 3.13 nM），并且EP 2/4特异性激动剂米索前列醇增加MUC 5AC mRNA水平，而EP 1/3特异性激动剂硫前列酮则无影响。有趣的是，EP 4介导的cAMP产生的EC 50值的cAMP浓度（685.1 +/- 14.9 pM）远高于EP 2（462.33 +/- 23.79 pM），表明EP 4与EP 2相比对PGE（2）具有更高的敏感性。此外，与野生型小鼠相比，在转录和翻译水平上，PGE（2）诱导的Muc 5ac过量产生在G蛋白信号调节因子（Rgs）4敲除（KO）小鼠中显著增加，并且与表达增强型绿色荧光蛋白（lenti：：eGFP）的慢病毒相比，在用表达RGS 4的慢病毒（lenti：：RGS 4）感染的Rgs 4 KO小鼠中，Muc 5ac过量产生被显著抑制。最后，我们证实PGE（2）可以通过EP 4受体诱导MUC 5AC过度表达，并且RGS 4可能在控制气道中MUC 5AC过度表达中具有抑制作用。这些发现可能为呼吸系统疾病新药的开发提供分子范例。
Song KS, Choi YH, Kim JM, Lee H, Lee TJ, Yoon JH. Suppression of prostaglandin E-2-induced MUC5AC overproduction by RGS4 in the airway. Am J Physiol Lung Cell Mol Physiol 296: L684-L692, 2009. First published February 6, 2009; doi:10.1152/ajplung.90396.2008.-The mechanism by which E-prostanoid (EP) receptor is critically involved in PGE(2)-induced mucin 5AC (MUC5AC) gene expression in the airway has been unclear. Furthermore, there have been little reports regarding the negative regulatory mechanism and/or proteins that affect PGE(2)-induced MUC5AC overproduction. In the present study, we found that PGE(2) induced MUC5AC gene expression in a dose-dependent manner (EC50: 73.31 +/- 3.13 nM) and that the EP2/4-specific agonist, misoprostol, increased MUC5AC mRNA level, whereas the EP1/3-specific agonist, sulprostone, had no effect. Interestingly, the cAMP concentration (685.1 +/- 14.9 pM) of the EC50 value of EP4-mediated cAMP production was much higher than that of EP2 (462.33 +/- 23.79 pM), suggesting that EP4 has higher sensitivity to PGE(2) compared with EP2. Moreover, PGE(2)-induced Muc5ac overproduction was much increased in regulator of G protein signaling (Rgs) 4 knockout (KO) mice compared with wild-type mice at both transcriptional and translational levels, and it was dramatically suppressed in Rgs4 KO mice that had been infected with lentivirus expressing RGS4 (lenti::RGS4) compared with lentivirus expressing enhanced green fluorescent protein (lenti:: eGFP). Finally, we demonstrate that PGE(2) can induce MUC5AC overproduction via the EP4 receptor and that RGS4 may have suppressive effects in controlling MUC5AC overexpression in the airway. These findings may provide a molecular paradigm for the development of novel drugs for respiratory diseases.