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Epithelial Cell IB-Kinase Has an Important Protective Role in Clostridium difficile Toxin A-Induced Mucosal Injury¹

Sungwon Chae^*, Lars Eckmann^*, Yukiko Miyamoto^*, Charalabos Pothoulakis, Michael Karin and Martin F. Kagnoff^2,*,

^* Department of Medicine, University of California at San Diego, La Jolla, CA 92093; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093; and Department of Pediatrics, University of California at San Diego, La Jolla, CA 92093

Toxin A released by Clostridium difficile interacts with the single layer of intestinal epithelial cells that lines the host’s intestinal tract and leads to mucosal damage and inflammation that manifests clinically as antibiotic-associated diarrhea and pseudomembranous colitis. Activation of the transcription factor NF-B in intestinal epithelial cells is important for regulating the expression of epithelial cell proinflammatory genes and cell survival. However, the role of NF-B activation in the pathogenesis of C. difficile toxin A-induced colitis is unknown. To determine the functional importance in vivo of NF-B activation in intestinal epithelium in the pathogenesis of C. difficile-induced colitis, we used mutant mice that do not activate the classical NF-B signaling pathway in intestinal epithelial cells due to a conditional deficiency in those cells of the IB-kinase (IKK) subunit of IKK. C. difficile toxin A challenge of intestinal loops in intestinal epithelial cell IKK-deficient mice induced a rapid and significant increase in intestinal epithelial apoptosis compared with littermate controls. This was accompanied by a significant increase in acute mucosal inflammation, mucosal injury, luminal fluid secretion, and bacterial translocation. We conclude that activation of intestinal epithelial cell NF-B by toxin A plays an important host mucosal protective role after C. difficile toxin A exposure that is mediated, at least in part, through promoting epithelial cell survival by abrogating epithelial cell apoptosis.

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