Flagellin/TLR5 responses in epithelia reveal intertwined activation of inflammatory and apoptotic pathways

• Type of Material: Article
• Authors: Hui Zeng, Emory University; Huixia Wu, Emory University; Valerie Sloane, Emory University; Rheinallt Jones, Emory University; Yimin Yu, Emory University; Patricia Denning, Emory University; Andrew Gewirtz, Emory University; Andrew Neish, Emory University
• Language: English
• Date: 2006-01-01
• Publisher: American Physiological Society
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2006 the American Physiological Society
• Final Published Version (URL): http://dx.doi.org/10.1152/ajpgi.00273.2005
• Title of Journal or Parent Work: AJP - Gastrointestinal and Liver Physiology
• ISSN: 0193-1857
• Volume: 290
• Issue: 1
• Start Page: G96
• End Page: G108
• Grant/Funding Information: This study was supported by National Institutes of Health Grants RO1 AI-51282 and AI-49741 (to A. S. Neish) and DK-062851 (to P. Lin), Emory Digestive Disease Research Center Grant R24 DK-064399, and the Woodruff Research Foundation.
• Keywords: GASTROENTEROLOGY & HEPATOLOGY; Life Sciences & Biomedicine; SIGNALING PATHWAY; IL-8 EXPRESSION; Salmonella; cDNA microarray; Gastroenterology & Hepatology; Toll-like receptor; Science & Technology; PROGRAMMED CELL-DEATH; PHYSIOLOGY; BACTERIA-FACED MACROPHAGES; NF-KAPPA-B; inflammation; TNF-ALPHA; KINASE; TOLL-LIKE RECEPTOR-5; INNATE IMMUNE-RESPONSE; SALMONELLA; Physiology
• Research Categories: Health Sciences, Pathology; Biology, Physiology; Biology, Molecular

Abstract

Flagellin, the primary structural component of bacterial flagella, is recognized by Toll-like receptor 5 (TLR5) present on the basolateral surface of intestinal epithelial cells. Utilizing biochemical assays of proinflammatory signaling pathways and mRNA expression profiling, we found that purified flagellin could recapitulate the human epithelial cell proinflammatory responses activated by flagellated pathogenic bacteria. Flagellin-induced proinflammatory activation showed similar kinetics and gene specificity as that induced by the classical endogenous proinflammatory cytokine TNF-α, although both responses were more rapid than that elicited by viable flagellated bacteria. Flagellin, like TNF-α, activated a number of antiapoptotic mediators, and pretreatment of epithelial cells with this bacterial protein could protect cells from subsequent bacterially mediated apoptotic challenge. However, when NF-κB-mediated or phosphatidylinositol 3-kinase/Akt proinflammatory signaling was blocked, flagellin could induce programmed cell death. Consistently, we demonstrate that flagellin and viable flagellate Salmonella induces both the extrinsic and intrinsic caspase activation pathways, with the extrinsic pathway (caspase 8) activated by purified flagellin in a TLR5-dependant fashion. We conclude that interaction of flagellin with epithelial cells induces caspase activation in parallel with proinflammatory responses. Such intertwining of proinflammatory and apoptotic signaling mediated by bacterial products suggests roles for host programmed cell death in the pathogenesis of enteric infections. Copyright © 2006 the American Physiological Society.