Interferon-γ-induced intestinal epithelial barrier dysfunction by NF-κB/HIF-1α pathway

Area of Science:

• Gastroenterology
• Immunology
• Cell Biology

Background:

• Intestinal barrier dysfunction is linked to Interferon-γ (IFN-γ) but underlying mechanisms remain unclear.
• Hypoxia-inducible factor-1 (HIF-1) is crucial in hypoxia and inflammation, impacting intestinal barrier integrity.

Purpose of the Study:

• To investigate if IFN-γ induces intestinal barrier dysfunction by regulating HIF-1α activation and function.
• To elucidate the role of the NF-κB pathway in IFN-γ-mediated HIF-1α regulation and barrier disruption.

Main Methods:

• T84 intestinal epithelial cells were treated with IFN-γ to assess HIF-1α and tight junction protein expression.
• NF-κB activation and inhibition were studied using pyrolidinedithiocarbamate (PDTC).
• Intestinal epithelial permeability and tight junction protein alterations were measured.

Main Results:

• IFN-γ increased HIF-1α expression in a time- and dose-dependent manner, linked to NF-κB activation.
• NF-κB inhibition suppressed HIF-1α expression and prevented IFN-γ-induced increases in permeability and tight junction depletion.
• IFN-γ-mediated NF-κB activation and tight junction modulation were significantly mediated by HIF-1α.

Conclusions:

• IFN-γ induces intestinal epithelial barrier dysfunction and tight junction disruption.
• This disruption is mediated by the upregulation of HIF-1α expression through the NF-κB pathway.