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-κB (NF-κB) 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-κB and cAMP responsive element-binding protein (CREB) in this response, the NF-κB inhibitory protein IκBα or a dominant negative mutant of CREB was co-transfected into cells and the data show that transfection of either IκBα or DN-CREB significantly attenuated ghrelin-induced COX-2 expression. Moreover ghrelin stimulated phosphorylation of CREB, which was mediated primarily via protein kinase Cδ activation. Furthermore, inhibition of PKCδ function significantly attenuated ghrelin-induced COX-2 expression. In addition, ghrelin stimulates phosphorylation of PKCδ. Together, these results indicate that in addition to NF-κB, protein kinase Cδ-mediated CREB activation plays an important role in the cellular responses of ghrelin. J. Cell. Biochem. 102: 1245–1255, 2007. © 2007 Wiley-Liss, Inc.