CD40 stimulates a "feed-forward" NF-?B-driven molecular pathway that regulates IFN-? expression in carcinoma cells.

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CD40 stimulates a "feed-forward" NF-?B-driven molecular pathway that regulates IFN-? expression in carcinoma cells.

J Immunol. 2012 Jun 1;188(11):5521-7

Authors: Moschonas A, Ioannou M, Eliopoulos AG

Abstract
IFN-? 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-? upregulation through an unconventional "feed-forward" mechanism, which is orchestrated by canonical NF-?B and involves the sequential de novo synthesis of IFN regulatory factor (IRF)1 and Viperin (RSAD2), an IRF1 target. RelA (p65) NF-?B, IRF1, and Viperin-dependent IRF7 binding to the IFN-? promoter largely controls its activity. However, full activation of IFN-? also requires the parallel engagement of noncanonical NF-?B2 signaling leading to p52 recruitment to the IFN-? promoter. These data define a novel link between CD40 signaling and IFN-? expression and provide a telling example of how signal propagation can be exploited to ensure efficient regulation of gene expression.

PMID: 22547704 [PubMed - indexed for MEDLINE]

NF-kB pathway NF-kB signaling NF-kappaB signaling pathway