Interferon-γ-Induced Intestinal Epithelial Barrier Dysfunction by NF-κB/HIF-1α Pathway

Interferon-gamma (IFN-gamma) plays an important role in intestinal barrier dysfunction. However, the mechanisms are not fully understood. As hypoxia-inducible factor-1 (HIF-1) is a critical determinant response to hypoxia and inflammation, which has been shown to be deleterious to intestinal barrier function, we hypothesized that IFN-gamma induces loss of barrier function through the regulation of HIF-1 alpha activation and function. In this study, we detected the expressions of HIF-1 alpha and tight junction proteins in IFN-gamma-treated T84 intestinal epithelial cell line. IFN-gamma led to an increase of HIF-1 alpha expression in time- and dose-dependent manners but did not change the expression of HIF-1 beta. The IFN-gamma-induced increase in HIF-1 alpha was associated with an activation of NF-kappa B. Treatment with the NF-kappa B inhibitor, pyrolidinedithiocarbamate (PDTC), significantly suppressed the activation of NF-kappa B and the expression of HIF-1 alpha. In addition, IFN-gamma also increased intestinal epithelial permeability and depletion of tight junction proteins; inhibition of NF-kappa B or HIF-1 alpha prevented the increase in intestinal permeability and alteration in tight junction protein expressions. Interestingly, we demonstrated that a significant portion of IFN-gamma activation NF-kB and modulation tight junction expression is mediated through HIF-1 alpha. Taken together, this study suggested that IFN-gamma induced the loss of epithelial barrier function and disruption of tight junction proteins, by upregulation of HIF-1 alpha expression through NF-kappa B pathway.