Interferon-γ Regulation of Intestinal Epithelial Permeability

Abstract

The maintenance and regulation of the barrier function of the epithelial lining of the intestine are important homeostatic events, serving to allow selective absorption from the gut lumen while simultaneously limiting the access of bacteria into the mucosa. Interferon-gamma is a pleiotrophic cytokine produced predominantly by natural kill cells and CD4+ T cells that under normal circumstances, and particularly during infection or inflammation, will be a component of the intestinal milieu. Use of colon-derived epithelial cell lines and, to a less extent, murine in vivo analyses, have revealed that interferon-gamma (IFN-gamma) can increase epithelial permeability as gauged by markers of paracellular permeability and bacterial transcytosis, with at least a portion of the bacteria using the transcellular permeation pathway. In this review, we describe the main characteristics of epithelial permeability and then focus on the ability of IFN-gamma to increase epithelial permeability, and the mechanism(s) thereof.

Interferon-γ-induced increases in intestinal epithelial macromolecular permeability requires the Src kinase Fyn

“…This may reflect differences in the efficacy of the pharmacologics but could also reflect differences in the signalling pathways that govern paracellular and transcellular permeability. Much remains to be done to precisely elucidate the IFNg signalling events that control epithelial barrier function, and whereas others have focused on defining TJ protein and cytoskeletal changes, [5][6][7][8] the present investigation is in accordance with IFNg modulation of epithelial endocytosis and transcellular permeability. 10 The delay in PI3K activity relative to initial STAT phosphorylation is intriguing and suggests mobilization of temporally and spatially distinct signalling pathways, a hypothesis supported by data showing that in T84 cells, neither Src kinase nor PI3K inhibition affected STAT1-dependent immune activities (IRF-1 expression and IP-10 secretion).…”

“…4 In addition to its pivotal role in immune regulation, numerous in vitro, and a lesser number of in vivo, studies reveal that IFNg decreases enteric epithelial barrier function. [5][6][7] IFNg-induced disruption of epithelial barrier function is accompanied by reduced expression of the tight junction (TJ) proteins, zonula occludens (ZO)-1 and occludin, 6,7 and this would allow increased permeation of material between adjacent cells via the paracellular pathway. 8 We, and others, have shown that IFNg can promote the transcytosis of bacteria across epithelial monolayers.…”

Spermidine Stimulates T Cell Protein-tyrosine Phosphatase-mediated Protection of Intestinal Epithelial Barrier Function

“…The compromising effect of IFN-␥ on the epithelial barrier is characterized by alterations in expression of the tight junction proteins occludin and ZO-1, resulting in increased transepithelial permeability and decreased TER (3,4,28,29,(31)(32)(33)(34). We have shown that coadministration of spermidine with IFN-␥ to epithelial monolayers significantly attenuated the IFN-␥-induced drop in TER and concurrent increases in epithelial permeability.…”

AMP-activated Protein Kinase Mediates the Interferon-γ-induced Decrease in Intestinal Epithelial Barrier Function

“…Recent studies have shown an involvement of PI3K in mediating the effects of IFN␥ on epithelial barrier properties (11,15). In contrast, a major role for the most established mediator of IFN␥ signaling, the signal transducer and activator of transcription 1, in epithelial barrier defects has not been confirmed (15,39,57). Here, we show that IFN␥ activates the cellular energy sensor, AMPK, in intestinal epithelial cells and that inhibition of AMPK diminishes the detrimental effect of this inflammatory cytokine on epithelial barrier function.…”