Interferon-gamma expression by intraepithelial lymphocytes results in a loss of epithelial barrier function in a mouse model of total parenteral nutrition

Objective To determine the etiology of the loss of epithelial barrier function observed with the administration of total parenteral nutrition (TPN) in a mouse model. Summary Background Data Removal of enteral nutrition with the administration of TPN is associated with a loss of intestinal epithelial barrier function. The etiology of this barrier loss is not clear. Because intraepithelial lymphocytes (IELs) produce a number of cytokines that may alter epithelial permeability, the authors investigated IEL cytokine expression in a mouse model of TPN. Methods Adult C57BL/6 mice received TPN or enteral diet for 7 days. IELs were subsequently harvested and the mRNA expression of cytokines was measured. Epithelial barrier function was assessed in vitro with Cr-51-EDTA in Ussing chambers and was expressed as the permeability coefficient (Papp). Results IEL mRNA expression of interferon-gamma (IFN-gamma) rose from 0.14 +/- 0.07 in the control (enterally fed) group to 0.44 +/- 0.11 attomoles/muL in the TPN group (P < .05). Transforming growth factor-beta1 declined slightly but not significantly, from 0.75 +/- 0.35 to 0.55 +/- 0.18 attomoles/muL in the control and TPN groups, respectively. Epithelial barrier function declined significantly with TPN compared to controls. To assess the relevance of IFN-gamma changes, permeability in IFN-gamma knockout mice was studied. Barrier function was significantly higher in IFN-gamma knockout mice on TPN compared to C57BU6 mice that received TPN. Conclusions IEL cytokine expression changes significantly with TPN administration. The partial correction with IFN-gamma knockout mice suggests that an upregulation of IFN-gamma expression is one mechanism responsible for the loss of the epithelial barrier associated with TPN.