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Infection and Immunity, February 1999, p. 608-617, Vol. 67, No. 2
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Orchestration of Neutrophil Movement by Intestinal Epithelial Cells in Response to Salmonella typhimurium Can Be Uncoupled from Bacterial Internalization

Andrew T. Gewirtz,1 Andrew M. Siber,2 James L. Madara,1 and Beth A. McCormick2,3,*

Combined Program in Pediatric Gastroenterology and Nutrition, Division of Mucosal Immunology, Massachusetts General Hospital,2 and Department of Pediatrics, Harvard Medical School,3 Boston, Massachusetts, and Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia1

Received 11 August 1998/Returned for modification 16 October 1998/Accepted 5 November 1998

Intestinal epithelial cells respond to Salmonella typhimurium by internalizing this pathogen and secreting, in a polarized manner, an array of chemokines which direct polymorphonuclear leukocyte (PMN) movement. Notably, interleukin-8 (IL-8) is secreted basolaterally and directs PMN through the lamina propria, whereas pathogen-elicited epithelial chemoattractant (PEEC) is secreted apically and directs PMN migration across the epithelial monolayer to the intestinal lumen. While most studies of S. typhimurium pathogenicity have focused on the mechanism by which this bacterium invades its host, the enteritis characteristically associated with salmonellosis appears to be more directly attributable to the PMN movement that occurs in response to this pathogen. Therefore, we sought to better understand the relationship between S. typhimurium invasion and epithelial promotion of PMN movement. First, we investigated whether S. typhimurium becoming intracellular was necessary or sufficient to induce epithelial promotion of PMN movement. Blocking S. typhimurium invasion by preventing, with cytochalasin D, the epithelial cytoskeletal rearrangements which mediate internalization did not reduce the epithelial promotion of PMN movement. Conversely, bacterial attainment of an intracellular position was not sufficient to induce model epithelia to direct PMN transmigration, since neither basolateral invasion by S. typhimurium nor apical internalization of an invasion-deficient mutant (achieved by inducing membrane ruffling with epidermal growth factor) induced this epithelial cell response. These results indicate that specific interactions between the apical surface of epithelial cells and S. typhimurium, rather than simply bacterial invasion, mediate the epithelial direction of PMN transmigration. To further investigate the means by which S. typhimurium induces epithelia to direct PMN movement, we investigated whether the same signaling pathways regulate secretion of IL-8 and PEEC. IL-8 secretion, but not PEEC secretion, was activated by phorbol myristate acetate and blocked by an inhibitor (mg-132) of the proteosome which mediates NF-kappa beta activation. Further, secretion of IL-8, but not PEEC, was activated by an entry-deficient (HilDelta ) S. typhimurium mutant or by basolateral invasion of a wild-type strain. Together, these results indicate that distinct signaling pathways mediate S. typhimurium invasion, induction of IL-8 secretion, and induction of PEEC secretion in model intestinal epithelia.

* Corresponding author. Mailing address: Combined Program in Pediatric Gastroenterology and Nutrition, Division of Mucosal Immunology, Massachusetts General Hospital, Charlestown Navy Yard Bldg. 149 (1493404) Charlestown, MA 02129. Phone: (617) 726-4168. Fax: (617) 726-4172. E-mail: mccormic{at}helix.mgh.harvard.edu.

Infection and Immunity, February 1999, p. 608-617, Vol. 67, No. 2
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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