Editors' ChoiceEpithelia

Breaching a Barrier

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Sci. Signal.  13 Oct 2009:
Vol. 2, Issue 92, pp. ec332
DOI: 10.1126/scisignal.292ec332

Crohn's disease (CD), a form of inflammatory bowel disease that results from the interplay of genetic, immunological, and bacterial factors, is associated with increased abundance of the proinflammatory cytokine interferon-γ (IFN-γ). IFN-γ disrupts the barrier function of intestinal epithelial cells, thereby increasing exposure of cells of the mucosal immune system to commensal bacteria, an effect that may be crucial to CD pathogenesis. Scharl et al. found that IFN-γ stimulated the activation (assessed by phosphorylation of Thr172 in the catalytic α1-subunit) of AMP (adenosine monophosphate)–activated protein kinase (AMPK) in polarized monolayers of human colonic T84 epithelial cells. Although AMPK is typically activated through a decline in ATP, and thus an increase in the ratio of AMP to ATP, its activation by IFN-γ was not associated with a significant change in intracellular ATP. Pharmacological inhibition of AMPK attenuated the decrease in transepithelial resistance caused by 72-hour treatment with IFN-γ, as did AMPK knockdown with siRNA; AMPK knockdown also diminished the IFN-γ−mediated increase in transepithelial permeability of fluorescently labeled dextran. Further analysis showed that AMPK knockdown inhibited the IFN-γ−mediated decrease in abundance of the tight junction proteins occludin and ZO-1, without inhibiting IFN-γ−mediated ZO-1 internalization. The authors thus conclude that AMPK plays a role in the IFN-γ−mediated breakdown of intestinal epithelial barrier function—and may therefore be involved in the pathogenesis of CD—through a mechanism that does not appear to depend on a decrease in cellular ATP.

M. Scharl, G. Paul, K. E. Barrett, D. F. McCole, AMP-activated protein kinase mediates the interferon-γ-induced decrease in intestinal epithelial barrier function. J. Biol. Chem. 284, 27952–27963 (2009). [Abstract] [Full Text]

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