CD40 stimulates a "feed-forward" NF-κB-driven molecular pathway that regulates IFN-β expression in carcinoma cells

IFN-β and the CD40L (CD154) share important roles in the antiviral and antitumor immune responses. In this study, we show that CD40 receptor occupancy results in IFN-β upregulation through an unconventional "feed-forward" mechanism, which is orchestrated by canonical NF-κB and involves the...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2012-06, Vol.188 (11), p.5521-5527
Main Authors: Moschonas, Aristides, Ioannou, Marina, Eliopoulos, Aristides G
Format: Article
Language:English
Subjects:
Carcinoma - genetics
Carcinoma - immunology
Carcinoma - pathology
CD40 Antigens - genetics
CD40 Antigens - physiology
Cell Line, Transformed
Cell Line, Tumor
Feedback, Physiological
Gene Expression Regulation - immunology
HEK293 Cells
Humans
Interferon-beta - biosynthesis
Interferon-beta - genetics
NF-kappa B - physiology
Signal Transduction - genetics
Signal Transduction - immunology
Urinary Bladder Neoplasms - genetics
Urinary Bladder Neoplasms - immunology
Urinary Bladder Neoplasms - pathology
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Summary:IFN-β and the CD40L (CD154) share important roles in the antiviral and antitumor immune responses. In this study, we show that CD40 receptor occupancy results in IFN-β upregulation through an unconventional "feed-forward" mechanism, which is orchestrated by canonical NF-κB and involves the sequential de novo synthesis of IFN regulatory factor (IRF)1 and Viperin (RSAD2), an IRF1 target. RelA (p65) NF-κB, IRF1, and Viperin-dependent IRF7 binding to the IFN-β promoter largely controls its activity. However, full activation of IFN-β also requires the parallel engagement of noncanonical NF-κB2 signaling leading to p52 recruitment to the IFN-β promoter. These data define a novel link between CD40 signaling and IFN-β expression and provide a telling example of how signal propagation can be exploited to ensure efficient regulation of gene expression.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1200133