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Abstract
Cyclooxygenase-2 (COX) 2 promotes intestinal wound healing but elicits also proinflammatory effects and has been implicated in colorectal carcinogenesis. Thus, a balanced expression of COX-2 is essential for intestinal homeostasis. This study was designed to evaluate the regulation of COX-2 by probiotic organisms and to characterize ligands and receptors involved. Colo320 and SW480 intestinal epithelial cells (IEC) were stimulated with gastrin or TNF-α and pre- or coincubated with commensales, bacterial supernatants, or distinct toll-like receptor (TLR) ligands. COX-2 promoter activity was determined by luciferase assays, protein expression by Western blotting, and secretion of prostaglandin E 2 (PGE 2 ) by ELISA. Commensales differentially regulated COX-2 expression in IEC. E. coli Nissle 1917, the probiotic mixture VSL#3, and media conditioned by these organisms ameliorated induced COX-2 expression and PGE 2 secretion. Heat inactivation and DNase treatment significantly decreased these regulatory capacities. Lactobacillus acidophilus, however, significantly increased COX-2 expression and PGE 2 secretion. TLR agonists differentially ameliorated basal or induced COX-2 expression. Distinct probiotics specifically and significantly decrease induced COX-2 expression in IEC, most likely mediated by released factors and in part by bacterial DNA. A significant involvement of TLRs in these regulatory processes remains to be established.
ACKNOWLEDGMENTS
This work has been performed at the Department of Medicine I, GI-Unit at the St. Josef-Hospital, University of Bochum in Bochum, Germany. Part of the experiments was furthermore kept out at the Department of Medicine II, Ludwig-Maximilians-University in Munich, Germany. The work was supported by grants from the Deutsche Forschungsgemeinschaft (OT 186/10-3 to J.-M. Otte), the FoRUM-Program at the University of Bochum (to J.-M. Otte), and a nonrestricted research grant from Ardeypharm GmbH, Herdecke, Germany. Plasmids were kindly provided by R. Medzhitov (hTLR2 and hTLR4; Yale, USA) and K. Miyake (MD-2; Saga Medical School, Japan). We are grateful for the excellent technical assistance of Rainer Lebert. Results of this study are part of the doctoral thesis of R. Mahjurian-Namari, were presented at the Digestive Disease Week 2005 in Chicago, and have been published in abstract form in Gastroenterology, Vol. 128, issue 4, pp. A219–A219 (Supplement).