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B p50, RelA, and cRel Subunits in Virus-Induced Type 1 IFN Expression1
* Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL 33612;
Department of Microbiology, Columbia University, New York, NY 10032;
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; and
Department of Microbiology, and Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10028
Type 1 IFNs (IFN-
) play pivotal roles in the host antiviral response and in TLR-induced signaling. IFN regulatory factor (IRF) and NF-
B transcription factors are thought to be crucial for virus-induced mRNA expression of IFN-. Although recent studies have demonstrated essential roles for IRF3 and IRF7, the definitive role of NF-B factors in IFN- (or IFN-) expression remains unknown. Using mice deficient in distinct members of the NF-B family, we investigated NF-B function in regulating type 1 IFN expression in response to Sendai virus and Newcastle disease virus infection. Surprisingly, IFN- and IFN- expression was strongly induced following virus infection of mouse embryonic fibroblasts (MEFs) from p50–/–, RelA/p65–/–, cRel–/–, p50–/–cRel–/–, and p50–/–RelA–/– mice. Compared with wild-type MEFs, only RelA–/– and p50–/–RelA–/– MEFs showed a modest reduction in IFN- expression. To overcome functional redundancy between different NF-B subunits, we expressed a dominant-negative IB protein in p50–/–RelA–/– MEFs to inhibit activation of remaining NF-B subunits. Although viral infection of these cells failed to induce detectable NF-B activity, both Sendai virus and Newcastle disease virus infection led to robust IFN- expression. Virus infection of dendritic cells or TLR9-ligand CpG-D19 treatment of plasmacytoid dendritic cells from RelA–/– or p50–/–cRel–/– mice also induced robust type 1 IFN expression. Our findings therefore indicate that NF-B subunits p50, RelA, and cRel play a relatively minor role in virus-induced type 1 IFN expression.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant R01 AI059715 and institutional funds from Moffitt Cancer Center (to A.A.B.) and National Institutes of Health U19AI62623 funded Center to Investigate Viral Immune Antagonism (to A.G.-S.).
2 Address correspondence and reprint requests to Dr. Amer A. Beg, Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, 12902 Magnolia Drive, Mail Stop: SRB-2, Tampa, FL 33612. E-mail address: amer.beg{at}moffitt.org
3 Abbreviations used in this paper: IKK, IB kinase; BMDC, bone marrow dendritic cell; cDC, conventional dendritic cell; DC, dendritic cell; IRF, IFN regulatory factor; MEF, mouse embryonic fibroblast; MIG, murine stem cell virus internal ribosome entry site; NDV, Newcastle disease virus; pDC, plasmacytoid DC; PRD, positive regulatory domain; RPA, RNase protection assay; SV, Sendai virus; WT, wild type.
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