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

Song KS, Choi YH, Kim JM, Lee H, Lee TJ, Yoon JH. Suppression of prostaglandin E2-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 PGE2-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 PGE2-induced MUC5AC overproduction. In the present study, we found that PGE2 induced MUC5AC gene expression in a dosedependent manner (EC50: 73.31 3.13 nM) and that the EP2/4specific 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 with EP2. Moreover, PGE2-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 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.