Synergistic eVects of interferon ã and tumour necrosis factor á on T84 cell function

Background—Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation and increased epithelial permeability. Both tumour necrosis factor á (TNF-á) and interferon ã (IFN-ã) have been implicated in IBD. Aims—To understand better the eVects of these cytokines on epithelial cell function. Methods—T84 cells were cultured with IFN-ã and TNF-á and changes in transepithelial resistance (TER), fluorescein isothiocyanate (FITC) dextran flux, short circuit current (Isc), cystic fibrosis transmembrane conductance regulator (CFTR) protein levels, cell morphology, TNF receptor gene expression, and apoptosis were assayed. Results—Relative to controls, significant changes (p<0.05) occurred in cells incubated with IFN-ã for two days: TER was decreased to 20 (6.2)%, FITC–dextran flux was increased by 109 (19)-fold, cAMP and Ca dependent Isc were decreased to 51 (6.4)% and 24 (2.2)%, respectively, and CFTR levels were decreased to 47 (11)%. Cell morphology was altered but cell death was not induced. TNF receptor mRNA levels were increased. When added with IFN-ã, TNF-á accelerated IFN-ã dependent changes. Relative to controls, significant changes occurred after one day of culture with IFN-ã plus TNF-á: TER was decreased to 27 (3.5)%, FITC–dextran flux was increased by 185 (45)-fold, and cAMP and Ca dependent Isc were decreased to 66 (12)% and 35 (6.8)%, respectively. TNF-á also enhanced IFN-ã dependent changes in cell morphology but did not induce cell death. Conclusion—IFN-ã alters T84 cell epithelial properties and TNF-á can enhance these eVects, perhaps due to IFN-ã dependent increases in TNF receptor gene expression. Overall, these studies suggest that in IBD, TNF-á may have synergistic eVects on IFN-ã mediated alterations of epithelial cell function. (Gut 1999;45:191–198)