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This Article Full Text Full Text (PDF) All Versions of this Article: 291/4/F741    most recent 00081.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Chen, M. C. Articles by Klumpp, D. J. Search for Related Content PubMed PubMed Citation Articles by Chen, M. C. Articles by Klumpp, D. J.

Urothelial lesion formation is mediated by TNFR1 during neurogenic cystitis

Departments of ¹Urology and ²Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois

Submitted 8 March 2006 ; accepted in final form 11 April 2006

Interstitial cystitis (IC) is a chronic bladder inflammatory disease of unknown etiology that shares similarities with Crohn's disease and psoriasis. IC, often regarded as a neurogenic cystitis, is associated with urothelial lesions that likely compromise the bladder permeability barrier and thereby contribute to patient morbidity. Here, we use a murine model of neurogenic cystitis to investigate the mechanism of urothelial lesion formation and find that urothelial apoptosis induces formation of lesions. Lesions formed in wild-type mice but not in mice deficient in TNF, TNF receptors, or mast cells. In urothelial cultures, only siRNAs targeting TNFR1, but not TNFR2, blocked TNF-induced apoptosis, indicating a primary role for TNFR1. Trans-epithelial resistance, a measure of bladder barrier function, decreased during neurogenic cystitis in wild-type and TNFR2^–/– mice but was stabilized in TNF^–/– mice. Anti-TNF antibodies both altered bladder mast cell localization and stabilized barrier function. Based on these findings, we conclude that mast cell activation and release of TNF drive urothelial apoptosis and lesion formation in a murine neurogenic cystitis model, and we hypothesize that anti-TNF therapy may stabilize bladder barrier function in IC patients.

bladder barrier function; interstitial cystitis; apoptosis; urothelium

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