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Infection and Immunity, June 2004, p. 3179-3186, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3179-3186.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Toll-Like Receptor 4 Expression and Cytokine Responses in the Human Urinary Tract Mucosa

Patrik Samuelsson,1 Long Hang,1 Björn Wullt,1,2 Heikki Irjala,1,3 and Catharina Svanborg1*

Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology,1 Department of Urology, Lund University, Lund, Sweden,2 Department of Otorhinolaryngology and Head and Neck Surgery, University of Turku, Turku, Finland3

Received 26 November 2003/ Returned for modification 2 February 2004/ Accepted 13 February 2004

Mucosal pathogens trigger a local innate host response by activating epithelial cells. Bacterial adherence and Toll-like receptor 4 (TLR4) signaling have been implicated as key events in this process. This study addressed the molecular basis of the epithelial response to gram-negative infection in the human urinary tract. Mucosal biopsies were obtained from kidneys, ureters, and bladders of patients undergoing urinary tract surgery, and epithelial TLR4 and CD14 expression was examined by immunohistochemistry. TLR4 was detected in epithelial cells lining the entire urinary tract and in the renal tubular epithelium. CD14, in contrast, was completely absent from the epithelial tissue. The response of the epithelial cells to infection was studied by in vitro challenge of the biopsies with uropathogenic Escherichia coli bacteria. A rapid cytokine response was observed, with production of interleukin-1ß (IL-1ß), IL-6, and IL-8 but not of IL-4 or gamma interferon. Adhering, P- or type 1-fimbriated E. coli activated IL-6 and IL-8 production more efficiently than the nonfimbriated control, as shown by cellular staining and analysis of secreted cytokines. The results demonstrate that human uroepithelial cells possess the molecular machinery needed to respond to uropathogenic E. coli. This includes recognition receptors for fimbriae and TLR4 for transmembrane signaling. We speculate that the lack of membrane-bound CD14 allows the epithelium to regulate its sensitivity to lipopolysaccharide and to discriminate between more-virulent and less-virulent strains.

* Corresponding author. Mailing address: Department of Laboratory Medicine, Division of Microbiology, Immunology and Glycobiology, Lund University, Sölvegatan 23, S-223 62 Lund, Sweden. Phone: 46 46 173282. Fax: 46 46 137468. E-mail: Catharina.Svanborg{at}mig.lu.se.

Editor: A. D. O'Brien

Infection and Immunity, June 2004, p. 3179-3186, Vol. 72, No. 6
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.6.3179-3186.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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