Song Kyoung Seob, Choi Yeon Ho, Kim Jong-Mu, Lee Hyunjae, Lee Tae-Jin, Yoon Joo-Heon
Yonsei University College of Medicine, Seoul 120-752, Korea.
Am J Physiol Lung Cell Mol Physiol. 2009 Apr;296(4):L684-92. doi: 10.1152/ajplung.90396.2008. Epub 2009 Feb 6.
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 (EC(50): 73.31 +/- 3.13 nM) and that the EP(2/4)-specific agonist, misoprostol, increased MUC5AC mRNA level, whereas the EP(1/3)-specific agonist, sulprostone, had no effect. Interestingly, the cAMP concentration (685.1 +/- 14.9 pM) of the EC(50) value of EP(4)-mediated cAMP production was much higher than that of EP(2) (462.33 +/- 23.79 pM), suggesting that EP(4) has higher sensitivity to PGE(2) compared with EP(2). 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 EP(4) 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.
前列环素（EP）受体在气道中参与前列腺素E2（PGE2）诱导的粘蛋白5AC（MUC5AC）基因表达的机制尚不清楚。此外，关于影响PGE2诱导的MUC5AC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PGE2以剂量依赖性方式诱导MUC5AC基因表达（半数有效浓度：73.31±3.13 nM），并且EP（2/4）特异性激动剂米索前列醇可增加MUC5AC mRNA水平，而EP（1/3）特异性激动剂舒前列素则无作用。有趣的是，EP（4）介导的cAMP产生的半数有效浓度（EC50）值的cAMP浓度（685.1±14.9 pM）远高于EP（2）（462.33±23.79 pM），表明与EP（2）相比，EP（4）对PGE2具有更高的敏感性。此外，在转录和翻译水平上，与野生型小鼠相比，G蛋白信号调节剂（Rgs）4基因敲除（KO）小鼠中PGE2诱导的Muc5ac过量产生显著增加，并且与表达增强型绿色荧光蛋白的慢病毒（lenti::eGFP）相比，在感染了表达RGS4的慢病毒（lenti::RGS4）的Rgs4 KO小鼠中，PGE2诱导的Muc5ac过量产生被显著抑制。最后，我们证明PGE2可通过EP（4）受体诱导MUC5AC过量产生，并且RGS4可能在控制气道中MUC5AC过表达方面具有抑制作用。这些发现可能为开发新型呼吸系统疾病药物提供分子范例。
