Suppression of prostaglandin E2-induced MUC5AC overproduction by RGS4 in the airway

1 The Airway Mucus Institute, 2 Department of Otorhinolaryngology, 3 Brain Korea 21 for Medical Sciences, and 4 Research Center for Human Natural Defense System, Yonsei University College of Medicine, Seoul; and 5 Department of Anatomy, College of Medicine, Yeungnam University, Taegu, Korea Submitted 24 July 2008 ; accepted in final form 31 January 2009 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. inflammation; mucin 5AC; EP 4 ; regulator of G protein signaling-4 Address for reprint requests and other correspondence: J.-H. Yoon, Dept. of Otorhinolaryngology, Yonsei Univ. College of Medicine, 134 Shinchon-Dong, Seodaemun-gu, Seoul 120-752, Korea (e-mail: jhyoon{at}yuhs.ac )