Suppression of prostaglandin E2-induced MUC5AC overproduction by RGS4 in the airway.
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.
Song
Kyoung Seob
KS
Yonsei University College of Medicine, Seoul 120-752, Korea.
Choi
Yeon Ho
YH
Kim
Jong-Mu
JM
Lee
Hyunjae
H
Lee
Tae-Jin
TJ
Yoon
Joo-Heon
JH
D000818:Animals; D002460:Cell Line; D015232:Dinoprostone / Q000494:pharmacology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006801:Humans; D051379:Mice; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism*; D020710:RGS Proteins / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014132:Trachea / Q000378:metabolism*
C524678:MUC5AC protein, human; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; C545650:PTGER4 protein, human; C545651:Ptger4 protein, mouse; D020710:RGS Proteins; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; C098799:RGS4 protein; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019205:GTP-Binding Protein alpha Subunits, Gs; D015232:Dinoprostone