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This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/F1372    most recent 00472.2006v1 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.

RANTES mediates TNF-dependent lamina propria mast cell accumulation and barrier dysfunction in neurogenic cystitis

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

Submitted 29 November 2006 ; accepted in final form 17 January 2007

Barrier dysfunction of the urinary bladder is postulated to contribute to patient morbidity in the bladder inflammatory disease interstitial cystitis (IC). IC is often considered a neurogenic cystitis, but the mechanisms underlying barrier dysfunction are unclear. In murine neurogenic cystitis induced by pseudorabies virus (PRV), we previously observed formation of urothelial lesions characterized by urothelial apoptosis and urothelial discontinuities. Lesion formation was preceded by mast cell trafficking to the lamina propria, and trafficking was mediated by tumor necrosis factor- (TNF). Here, we found that supernatants of TNF-treated urothelial cultures promoted chemotaxis of bone marrow-derived mast cells in vitro that was blocked by anti-RANTES antibodies but unaffected by anti-TNF antibodies. In vivo, PRV infection of wild-type mice induced RANTES expression in the urothelium that was temporally coincident with lamina propria mast cell accumulation (maximum at days 3–4 following infection) and was not induced in TNF^–/– mice, TNFR1/2^–/– mice, or mice treated with anti-TNF antibodies. Anti-RANTES antibodies blocked PRV-induced lamina propria mast cell accumulation 56% and reduced the prevalence of animals with detectable lesions 42%, relative to isotype control antibodies. Bladder barrier function was quantified by measuring transepithelial resistance (TER). PRV induced a 49% loss of TER in the presence of control antibodies, but mice treated with anti-RANTES antibodies exhibited reduced TER loss (16%, P < 0.01). These data demonstrate that RANTES plays a key role in the pathogenesis of neurogenic cystitis and suggest that chemokines may represent novel therapeutic targets for IC patients with mast cell-associated disease.

transepithelial resistance; psoriasis; irritable bowel disease

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