Interleukin-1β Mediates β-Catenin-Driven Downregulation of Claudin-3 and Barrier Dysfunction in Caco2 Cells

IL-1 beta is a cytokine involved in mediating epithelial barrier dysfunction in the gut. It is known that IL-1 beta mediates activation of non-muscle myosin light chain kinase in epithelial cells, but the precise mechanism by which epithelial barrier dysfunction is induced by IL-1 beta is not understood. Using a Caco2 cell model, we show that the expression of the tight junction protein, claudin-3, is transcriptionally downregulated by IL-1 beta treatment. In addition, after assessing protein and mRNA expression, and protein localization, we show that inhibition of nmMLCK rescues IL-1 beta-mediated decrease in claudin-3 expression as well as junction protein redistribution. Using chromatin immunoprecipitation assays, we also show that beta-catenin targeting of the claudin-3 promoter occurs as a consequence of IL-1 beta-mediated epithelial barrier dysfunction, and inhibition of nmMLCK interferes with this interaction. Taken together, these data represent the first line of evidence demonstrating nmMLCK regulation of claudin-3 expression in response to IL-1 beta-treated epithelial cells.