Protein kinase Cdelta-mediated CREB activation regulates ghrelin-induced cyclooxygenase-2 expression and prostaglandin E2 production in human colonic epithelial cells.
Ghrelin, a newly identified gastric peptide, is known for its potent activity in growth hormone release and appetite. Our recent study showed that ghrelin could stimulate protein kinase C-mediated activation of nuclear factor-kappaB (NF-kappaB) and interleukin-8 secretion in human colonic epithelial cells transfected with a functional ghrelin receptor. In the present study, the effect of ghrelin stimulation on cyclooxygenese-2 expression and prostaglandin E2 production was examined. The data indicate that ghrelin significantly increased the levels of cyclooxygenase-2 (COX-2) protein as well as its promoter activity, which leaded to profound increase in prostaglandin E2 secretion. In order to examine the involvement of NF-kappaB and cAMP responsive element-binding protein (CREB) in this response, the NF-kappaB inhibitory protein IkappaBalpha or a dominant negative mutant of CREB was co-transfected into cells and the data show that transfection of either IkappaBalpha or DN-CREB significantly attenuated ghrelin-induced COX-2 expression. Moreover ghrelin stimulated phosphorylation of CREB, which was mediated primarily via protein kinase Cdelta activation. Furthermore, inhibition of PKCdelta function significantly attenuated ghrelin-induced COX-2 expression. In addition, ghrelin stimulates phosphorylation of PKCdelta. Together, these results indicate that in addition to NF-kappaB, protein kinase Cdelta-mediated CREB activation plays an important role in the cellular responses of ghrelin.
Zhao
Dezheng
D
Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. dzhao@bidmc.harvard.edu
D003106:Colon / Q000166:cytology / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000032:analysis / Q000096:biosynthesis*; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000378:metabolism*; D017930:Genes, Reporter; D054439:Ghrelin / Q000494:pharmacology*; D006801:Humans; D049410:Luciferases, Renilla / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051745:Protein Kinase C-delta / Q000378:metabolism*
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D054439:Ghrelin; D049410:Luciferases, Renilla; D051546:Cyclooxygenase 2; D051745:Protein Kinase C-delta; D015232:Dinoprostone