Submitted on July 24, 2008
Revised on January 21, 2009
Accepted on January 31, 2009
Suppression of prostaglandin E2-induced MUC5AC overproduction by RGS4 in the airway
Kyoung Seob Song1, Yeon Ho Choi1, Jong-Mu Kim1, Hyunjae Lee1, Tae-Jin Lee2, and Joo-Heon Yoon1*
1 Yonsei University College of Medicine
2 Yeungnam University
* To whom correspondence should be addressed. E-mail: jhyoon{at}yuhs.ac.
The mechanism by which EP receptor is critically involved in PGE2-induced MUC5AC gene expression in the airway has been unclear. Furthermore, there have been little reports regarding the negative regulatory mechanism and/or proteins which affect PGE2-induced MUC5AC overproduction. In the present study, we found that PGE2 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 PGE2 compared to EP2. Moreover, PGE2-induced Muc5ac overproduction was much increased in Regulator of G-protein signaling (Rgs) 4 KO mice compared to wild-type mice at both transcriptional and translational levels and it was dramatically suppressed in Rgs4 KO mice that had been infected with lenti::RGS4 compared to lenti::eGFP. Finally, we demonstrate that PGE2 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.
