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Infection and Immunity, October 2004, p. 5832-5839, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5832-5839.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Bacteroides fragilis Enterotoxin Induces Intestinal Epithelial Cell Secretion of Interleukin-8 through Mitogen-Activated Protein Kinases and a Tyrosine Kinase-Regulated Nuclear Factor-{kappa}B Pathway

Shaoguang Wu,1 Jan Powell,2 Nes Mathioudakis,1 Sheryl Kane,1 Ellen Fernandez,2 and Cynthia L. Sears1,3*

Divisions of Infectious Diseases,1 Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine,3 Department of Epidemiology, University of Maryland School of Medicine, Baltimore, Maryland2

Received 31 December 2003/ Returned for modification 27 January 2004/ Accepted 7 July 2004

Enterotoxigenic Bacteroides fragilis (ETBF) secretes a 20-kDa metalloprotease toxin termed B. fragilis toxin (BFT). ETBF disease in animals is associated with an acute inflammatory response in the intestinal mucosa, and lethal hemorrhagic colitis may occur in rabbits. In this study, we confirmed recent reports (J. M. Kim, Y. K. Oh, Y. J. Kim, H. B. Oh, and Y. J. Cho, Clin. Exp. Immunol. 123:421-427, 2001; L. Sanfilippo, C. K. Li, R. Seth, T. J. Balwin, M. J. Menozzi, and Y. R. Mahida, Clin. Exp. Immunol. 119:456-463, 2000) that purified BFT stimulates interleukin-8 (IL-8) secretion by human intestinal epithelial cells (HT29/C1 cells) and demonstrate that stimulation of IL-8 production is dependent on biologically active BFT and independent of serum. Induction of IL-8 mRNA expression occurs rapidly and ceases by 6 h after BFT treatment, whereas IL-8 secretion continues to increase for at least 18 h. Our data suggest that BFT-stimulated IL-8 secretion involves tyrosine kinase-dependent activation of nuclear factor-{kappa}B (NF-{kappa}B) as well as activation of the mitogen-activated protein kinases (MAPKs), p38 and extracellular signal-related kinase. Simultaneous activation of NF-{kappa}B and MAPKs appears necessary for secretion of IL-8 by HT29/C1 cells treated with BFT.

* Corresponding author. Mailing address: Division of Infectious Diseases, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross Bldg., Rm. 1167, Baltimore, MD 21205. Phone: (410) 614-0141. Fax: (410) 614-9775. E-mail: csears{at}jhmi.edu.

Editor: W. A. Petri, Jr.

Infection and Immunity, October 2004, p. 5832-5839, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5832-5839.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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