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(+)CD45RB(hi) 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(+)CD45RB(hi) 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(+)CD45RB(hi) 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 beta (TGF-beta) levels and net ion transport inversely correlated with tumor necrosis factor alpha (TNF-alpha) levels, pointing to the protective effect of IL-10 and TGF-beta and to a damaging effect of TNF-alpha. 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(+)CD45RB(hi) 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.
Division of Gastroenterology, University Hospital, Leuven, Belgium.
Peter
P
Suenaert
Philippe
P
Maerten
Gert
G
Van Assche
Willy
W
Van Driessche
Karel
K
Geboes
Veerle
V
Bulteel
Jeannine
J
Simaels
Patrick
P
Augustijns
Jan L
JL
Ceuppens
Paul
P
Rutgeerts
Clémentine
C
Perrier
D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003092:Colitis / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D007213:Indomethacin / Q000276:immunology / Q000494:pharmacology; D016753:Interleukin-10 / Q000032:analysis / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology*; D017136:Ion Transport / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D013154:Spleen / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology
D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D017493:Leukocyte Common Antigens; D007213:Indomethacin