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J. Biol. Chem., Vol. 280, Issue 22, 21237-21245, June 3, 2005

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Clostridium difficile Toxin A Regulates Inducible Cyclooxygenase-2 and Prostaglandin E₂ Synthesis in Colonocytes via Reactive Oxygen Species and Activation of p38 MAPK^*

Ho Kim, Sang Hoon Rhee, Efi Kokkotou, Xi Na, Tor Savidge, Mary P. Moyer¶, Charalabos Pothoulakis, and J. Thomas LaMont||

From the Division of Gastroenterology, Beth Israel Deaconess Medical Center, and the Department of Pediatrics Gastroenterology and Nutrition, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02215 and ^¶INCELL Corp., San Antonio, Texas 78249

Clostridium difficile toxin A induces acute colitis with neutrophil infiltration and up-regulation of numerous pro-inflammatory mediators, but the contribution of cyclooxygenase-2 (COX-2) induction in this infection is unknown. We report here that toxin A induces expression of COX-2 and secretion of prostaglandin E₂ (PGE₂) in a dose- and time-dependent manner in cultured NCM460 human colonocytes and in human intestinal xenografts. This induction was blocked by SB203580, a p38 MAPK inhibitor, which also decreased the phosphorylation of MSK-1, CREB/ATF-1, and COX-2 promoter activity following toxin A stimulation. Gel shift assays indicated that CREB/ATF-1 was the major proteins binding to the COX-2-CRE. Moreover, colonocytes exposed to toxin A produced reactive oxygen species (ROS), which activated p38 MAPK, MSK-1, and CREB/ATF-1, leading to subsequent COX-2 induction and PGE₂ secretion. In intact mice, blockage of p38 MAPK inhibited toxin A-mediated induction of COX-2 in enterocytes as well as lamina propria cells, and significantly blocked the toxin A-induced ileal secretion of fluid and PGE₂. Furthermore, a selective COX-2 inhibitor also diminished toxin A-associated ileal fluid and PGE₂ secretion. The main signaling pathway for toxin A induction of human COX-2 involves ROS-mediated activation of p38 MAPK, MSK-1, CREB, and ATF-1. Toxin A triggers ileal inflammation and secretion of fluid via COX-2 induction and release of PGE₂.

Received for publication, December 8, 2004 , and in revised form, February 15, 2005.

^* This work was supported by Research Grants DK R37-38458 (to J. T. L.) and DK RO1-33506 (to T. S. and C. P.) from the National Institutes of Health and by the Crohn's and Colitis Foundation of America, Inc. (to T. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Beth Israel Deaconess Medical Center, Division of Gastroenterology, Dana 501, 330 Brookline Ave., Boston, MA 02215. Tel.: 617-667-8377; Fax: 617-667-2767; E-mail: jlamont{at}bidmc.harvard.edu.

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