Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0607358 on December 26, 2007

Published online before print December 26, 2007
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(Journal of Leukocyte Biology. 2008;83:493-498.)
© 2008 by Society for Leukocyte Biology

The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation

Steven C. Gribar, Rahul J. Anand, Chhinder P. Sodhi and David J. Hackam1

Division of Pediatric Surgery, Department of Surgery, Children’s Hospital of Pittsburgh and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

1Correspondence: Division of Pediatric Surgery, Room 4A-486 DeSoto Wing, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213, USA. E-mail: david.hackam{at}chp.edu

ABSTRACT

Emerging evidence suggests that the innate immune system, comprised of Toll-like receptors (TLRs) and their associated molecules, plays a pivotal role in the regulation of intestinal inflammation and in the response to invading pathogens. Although TLRs are thought to have predominantly beneficial effects in pathogen recognition and bacterial clearance by leukocytes, their dysregulation and unique signaling effects within intestinal epithelia in the setting of inflammation may have devastating consequences. For instance, activation of TLR4 in enterocytes leads to an inhibition of enterocyte migration and proliferation as well as the induction of enterocyte apoptosis—factors that would be expected to promote intestinal injury while inhibiting intestinal repair. TLR signaling has been shown to be abnormal in several intestinal inflammatory diseases, including Crohn’s disease, ulcerative colitis, and necrotizing enterocolitis. This review serves to examine the evidence regarding the patterns of expression and signaling of TLRs in the intestinal mucosa at basal levels and during physiologic stressors to gain insights into the pathogenesis of intestinal inflammation. We conclude that the data reviewed suggest that epithelial TLR signaling—acting in concert with TLR signaling by leukocytes—participates in the development of intestinal inflammation. We further conclude that the evidence reviewed provides a rationale for the development of novel, epithelial-specific, TLR-based agents in the management of diseases of intestinal inflammation.

Key Words: lipopolysaccharide • mucosa • enterocyte • necrotizing enterocolitis • inflammatory bowel disease






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