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Infection and Immunity, October 2008, p. 4498-4508, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.01317-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Campylobacter-Induced Interleukin-8 Secretion in Polarized Human Intestinal Epithelial Cells Requires Campylobacter-Secreted Cytolethal Distending Toxin- and Toll-Like Receptor-Mediated Activation of NF-B

Jie Zheng,¹ Jianghong Meng,¹ Shaohua Zhao,³ Ruby Singh,³ and Wenxia Song^2*

Department of Nutrition and Food Science,¹ Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742,² Center for Veterinary Medicine, Office of Research, Food and Drug Administration, Laurel, Maryland 20708³

Received 28 September 2007/ Returned for modification 7 December 2007/ Accepted 7 July 2008

Campylobacter jejuni and Campylobacter coli colonize and infect the intestinal epithelium and cause acute inflammatory diarrhea. The intestinal epithelium serves as a physical barrier to, and a sensor of, bacterial infection by secreting proinflammatory cytokines. This study examined the mechanisms for Campylobacter-induced secretion of the proinflammatory chemokine interleukin-8 (IL-8) by using polarized T84 human colonic epithelial cells as a model. C. jejuni increased the secretion of both IL-8 and tumor necrosis factor alpha (TNF-) in polarized epithelial cells. However, the increase in IL-8 secretion was independent of Campylobacter-stimulated TNF- secretion. Polarized T84 cells secreted IL-8 predominantly to the basolateral medium independently of the inoculation direction. While there was a significant correlation between the levels of IL-8 secretion and Campylobacter invasion, all 11 strains tested increased IL-8 secretion by polarized T84 cells despite their differences in adherence, invasion, and transcytosis efficiencies. Cell-free supernatants of Campylobacter-T84-cell culture increased IL-8 secretion to levels similar to those induced by live bacterial inoculation. The ability of the supernatant to induce IL-8 secretion was reduced by flagellum and cytolethal distending toxin (CDT) gene mutants, treatment of the supernatant with protease K or heat, or treatment of T84 cells with the Toll-like receptor (TLR) inhibitor MyD88 inhibitory peptide or chloroquine. NF-B inhibitors or cdtB mutation plus MyD88 inhibitor, but not flaA cdtB double mutations, abolished the ability of the supernatant to induce IL-8 secretion. Taken together, our results demonstrate that Campylobacter-induced IL-8 secretion requires functional flagella and CDT and depends on the activation of NF-B through TLR signaling and CDT in human intestinal epithelial cells.

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* Corresponding author. Mailing address: Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742. Phone: (301) 405-7552. Fax: (301) 314-9489. E-mail: wenxsong{at}umd.edu

Published ahead of print on 21 July 2008.

Editor: V. J. DiRita

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Infection and Immunity, October 2008, p. 4498-4508, Vol. 76, No. 10
0019-9567/08/$08.00+0     doi:10.1128/IAI.01317-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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