Negative Feedback Regulation of IFN-γ Pathway by IFN Regulatory Factor 2 in Esophageal Cancers

Abstract

IFN-; is an antitumor cytokine that inhibits cell proliferation and induces apoptosis after engagement with the IFN-; receptors (IFNGR) expressed on target cells, whereas IFN regulatory factor 2 (IRF-2) is able to block the effects of IFN-; by repressing transcription of IFN-;-induced genes. Thus far, few studies have explored the influences of IFN-; on human esophageal cancer cells. In the present study, therefore, we investigated in detail the functions of IFN-; in esophageal cancer cells. The results in clinical samples of human esophageal cancers showed that the level of IFN-; was increased in tumor tissues and positively correlated with tumor progression and IRF-2 expression, whereas the level of IFNGR1 was decreased and negatively correlated with tumor progression and IRF-2 expression. Consistently, in vitro experiments showed that low concentration of IFN-; induced the expression of IRF-2 with potential promotion of cell growth, and moreover, IRF-2 was able to suppress IFNGR1 transcription in human esophageal cancer cells by binding a specific motif in IFNGR1 promoter, which lowered the sensitivity of esophageal cancer cells to IFN-;. Taken together, our results disclosed a new IRF-2-mediated inhibitory mechanism for IFN-;-induced pathway in esophageal cancer cells: IFN-; induced IRF-2 upregulation, then up-regulated IRF-2 decreased endogenous IFNGR1 level, and finally, the loss of IFNGR1 turned to enhance the resistance of esophageal cancer cells to IFN-;. Accordingly, the results implied that IRF-2 might act as a mediator for the functions of IFN-; and IFNGR1 in human esophageal cancers.

A novel approach to rescue immune escape in oral squamous cell carcinoma: Combined use of interferon-γ and LY294002

“…The molecular basis of these effects is the Stat1-dependent activation of gene encoding inhibitors that influence cellular progression (18,19). In contrast, our group found that IFN-Á promotes the proliferation of tumor cells in OSCC.…”

IFN Regulatory Factor 10 Is a Negative Regulator of the IFN Responses in Fish

“…However, the regulatory effects of IRF1 and IRF2 on IFN transcription are completely opposite. IRF1 is found to upregulate the expression of IFN-b and IFN-g, whereas IRF2 inhibits this induction, acting as an antagonist for IRF1 (26,28,34). Similarly, IRF4, competing with IRF5 for MyD88 interaction, markedly decreases the induction of proinflammatory cytokines and ISRE-Luc (52).…”

“…IRF2 and IRF4 are known negative regulators. IRF2 shares high sequence homology with IRF1 and serves as a transcriptional repressor of expression of IFN and ISGs by competing with IRF1 (26)(27)(28). IRF4 interacts with IRF5 and balances the antiviral responses when host cells were infected by virus (29,30).…”

Dual Faces of IFNγ in Cancer Progression: A Role of PD-L1 Induction in the Determination of Pro- and Antitumor Immunity

“…The inhibitory effect of aGalCer on B16F10 lung metastases, of which IFNg is known to be a critical mediator, is significantly more prominent in mice with mutations in tyrosine-441 of the IFNg receptor subunit 1 (31). The IFNg pathway has been demonstrated to be negatively regulated by IFN regulatory factor 2 in esophageal cancer (32).…”