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Infection and Immunity, September 2004, p. 5052-5062, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5052-5062.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Cooperative Interactions between Flagellin and SopE2 in the Epithelial Interleukin-8 Response to Salmonella enterica Serovar Typhimurium Infection

Fu-Chen Huang,1,2 Adam Werne,1 Qian Li,1 Edouard E. Galyov,3 W. Allan Walker,1 and Bobby J. Cherayil1*

Mucosal Immunology Laboratory, Pediatric Gastroenterology and Nutrition Unit, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts,1 Department of Pediatrics, Chang Gung Memorial Hospital, Kaohsiung, Taiwan,2 Division of Environmental Microbiology, Institute for Animal Health, Compton Laboratory, Berkshire, United Kingdom3

Received 26 March 2004/ Accepted 14 May 2004

Flagellin is an important stimulus for epithelial interleukin-8 (IL-8) secretion because of its ability to activate Toll-like receptor 5 (TLR5). SopE2, a Salmonella guanine nucleotide exchange factor (GEF), is also involved in intestinal inflammation. To clarify the proinflammatory mechanisms of these proteins, we examined their effects on IL-8 secretion and intracellular signaling in T84 epithelial cells. A Salmonella strain lacking SopE2 (and its homolog SopE) induced lower levels of IL-8 than the wild type and exhibited reduced activation of mitogen-activated protein kinases (MAPKs). Overexpression of wild-type SopE2 in this strain restored MAPK activation and augmented IL-8 production, whereas a mutant lacking GEF activity failed to increase IL-8 expression. Additional effects on signaling were demonstrated in transient transfection experiments, in which SopE2 enhanced the ability of TRAF6, a signal transducer downstream of TLR5, to activate the NF-{kappa}B transcription factor in 293 cells. Flagellin was also found to be required for IL-8 induction in T84 cells. In its absence, the ability of SopE2 overexpression to increase IL-8 secretion was impaired. Part of this impairment was related to the decreased motility of the flagellin-deficient strain, but lack of flagellin also affected translocation of SopE2 into the infected cells. Our results indicate that flagellin and SopE2 interact functionally at multiple levels to increase IL-8 secretion by epithelial cells—flagellin facilitating the translocation of SopE2, and SopE2 enhancing signaling pathways activated by flagellin. These observations offer a mechanistic explanation for the involvement of these proteins in the pathogenesis of Salmonella-induced gastroenteritis.

* Corresponding author. Mailing address: Pediatric Gastroenterology Unit, Room 3400, MGH East, Building 114, 16th Street, Charlestown, MA 02129. Phone: (617) 726-4170. Fax: (617) 726-4172. E-mail: cherayil{at}helix.mgh.harvard.edu.

Editor: A. D. O'Brien

Infection and Immunity, September 2004, p. 5052-5062, Vol. 72, No. 9
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.9.5052-5062.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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