Effects of T cell‐induced colonic inflammation on epithelial barrier function†

Background: Epithelial barrier disturbance is thought to contribute to the pathogenesis of inflammatory bowel diseases; however, it remains unclear whether it is a primary defect participating to the onset of inflammation or only a consequence of sustained inflammation. Methods: A time course study of epithelial barrier functions and immune mediators was performed in the CD4+CD45RBhi T cell transfer model of colitis using Ussing chambers. Results: In nonreconstituted severe combined immunodeficiency (SCID) mice, no epithelial dysfunction was observed. However, after transfer of CD4+CD45RBhi T cells or total CD4+ T cells, colon of SCID mice displayed a decreased epithelial resistance, even before overt microscopic inflammation had occurred. Sustained colitis of CD4+CD45RBhi T cell reconstituted mice was also associated with enhanced subepithelial resistance, enhanced paracellular permeability, and decreased net ion transport. All these reflect a disturbance of barrier function and may contribute to diarrhea. Epithelial resistance was positively correlated with interleukin 10 (IL‐10) and transforming growth factor &bgr; (TGF‐&bgr;) levels and net ion transport inversely correlated with tumor necrosis factor alpha (TNF‐&agr;) levels, pointing to the protective effect of IL‐10 and TGF‐&bgr; and to a damaging effect of TNF‐&agr;. Indomethacin, a nonselective COX inhibitor, decreased epithelial resistance independent of T cells and inflammation, but its effect was more pronounced in inflamed colon. Conclusions: Induction of colitis by transfer of CD4+CD45RBhi T cells in SCID mice leads to changes in the colonic epithelium before colitis develops. Decreased epithelium resistance might contribute to the development of colitis; however, it is not sufficient to lead to chronic inflammation. (Inflamm Bowel Dis 2010)

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