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and Tumor Necrosis Factor-
Synergize to Induce Intestinal Epithelial Barrier Dysfunction by Up-Regulating Myosin Light Chain Kinase Expression
From the Institute of Burn Research,* Southwest Hospital, Third Military Medical University, Chongqing, China; and the Department of Pathology, The University of Chicago, Chicago Illinois
Numerous intestinal diseases are characterized by immune cell activation and compromised epithelial barrier function. We have shown that cytokine treatment of epithelial monolayers increases myosin II regulatory light chain (MLC) phosphorylation and decreases barrier function and that these are both reversed by MLC kinase (MLCK) inhibition. The aim of this study was to determine the mechanisms by which interferon (IFN)-
and tumor necrosis factor (TNF)-
regulate MLC phosphorylation and disrupt epithelial barrier function. We developed a model in which both cytokines were required for barrier dysfunction. Barrier dysfunction was also induced by TNF- addition to IFN--primed, but not control, Caco-2 monolayers. TNF- treatment of IFN--primed monolayers caused increases in both MLCK expression and MLC phosphorylation, suggesting that MLCK is a TNF--inducible protein. These effects of TNF- were not mediated by nuclear factor-
B. However, at doses below those needed for nuclear factor-B inhibition, sulfasalazine was able to prevent TNF--induced barrier dysfunction, MLCK up-regulation, and MLC phosphorylation. Low-dose sulfasalazine also prevented morphologically evident tight junction disruption induced by TNF-. These data show that IFN- can prime intestinal epithelial monolayers to respond to TNF- by disrupting tight junction morphology and barrier function via MLCK up-regulation and MLC phosphorylation. These TNF--induced events can be prevented by the clinically relevant drug sulfasalazine.
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