Interferon-γ-induced intestinal epithelial barrier dysfunction by NF-κB/HIF-1α pathway.
Interferon-γ (IFN-γ) 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-γ induces loss of barrier function through the regulation of HIF-1α activation and function. In this study, we detected the expressions of HIF-1α and tight junction proteins in IFN-γ-treated T84 intestinal epithelial cell line. IFN-γ led to an increase of HIF-1α expression in time- and dose-dependent manners but did not change the expression of HIF-1β. The IFN-γ-induced increase in HIF-1α was associated with an activation of NF-κB. Treatment with the NF-κB inhibitor, pyrolidinedithiocarbamate (PDTC), significantly suppressed the activation of NF-κB and the expression of HIF-1α. In addition, IFN-γ also increased intestinal epithelial permeability and depletion of tight junction proteins; inhibition of NF-κB or HIF-1α prevented the increase in intestinal permeability and alteration in tight junction protein expressions. Interestingly, we demonstrated that a significant portion of IFN-γ activation NF-kB and modulation tight junction expression is mediated through HIF-1α. Taken together, this study suggested that IFN-γ induced the loss of epithelial barrier function and disruption of tight junction proteins, by upregulation of HIF-1α expression through NF-κB pathway.
1 Department of General Surgery, Xinqiao Hospital, Third Military Medical University , Chongqing, China .
Songwei
S
Yang
Min
M
Yu
Lihua
L
Sun
Weidong
W
Xiao
Xuechao
X
Yang
Ligang
L
Sun
Chaojun
C
Zhang
Yuanhang
Y
Ma
Hanwenbo
H
Yang
Yong
Y
Liu
Dingsong
D
Lu
Daniel H
DH
Teitelbaum
Hua
H
Yang
D000970:Antineoplastic Agents / Q000494:pharmacology; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis; D002460:Cell Line; D017097:Electric Impedance; D004789:Enzyme Activation / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D051550:I-kappa B Kinase / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000473:pathology*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D062725:Tight Junction Proteins / Q000276:immunology; D019108:Tight Junctions / Q000473:pathology*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000276:immunology*
D000970:Antineoplastic Agents; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D013859:Thiocarbamates; D062725:Tight Junction Proteins; D051996:Transcription Factor RelA; C066229:prolinedithiocarbamate; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D007371:Interferon-gamma; D011392:Proline; D051550:I-kappa B Kinase