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J. Biol. Chem., Vol. 279, Issue 43, 45194-45207, October 22, 2004

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Global and Distinct Targets of IRF-5 and IRF-7 during Innate Response to Viral Infection^*

Betsy J. Barnes, John Richards¶||, Margo Mancl, Sam Hanash**, Laura Beretta¶, and Paula M. Pitha

From the The Sidney Kimmel Comprehensive Cancer Center, the ^¶Department of Microbiology and Immunology and the ^**Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109 and the Department of Molecular Biology and Genetics, The Johns Hopkins University, Baltimore, Maryland 21231

The interferon regulatory factors (IRF) are transcriptional mediators of cellular response to viral invasion that play a critical role in the innate antiviral defense. Two of these factors, IRF-5 and IRF-7, play a critical role in the induction of interferon (IFNA) genes in infected cells; they are expressed constitutively in monocytes, B cells, and precursors of dendritic cells (pDC2) that are high producers of interferon , and their expression can be further stimulated by type I interferon. The goal of the present study was to identify and analyze expression of cellular genes that are modulated by IRF-5 and IRF-7 during the innate response to viral infection. The transcription profiles of infected BJAB cells overexpressing IRF-5 or IRF-7 were determined by using oligonucleotide arrays with probe sets representing about 6800 human genes. This analysis shows that IRF-5 and IRF-7 activate a broad profile of heterologous genes encoding not only antiviral, inflammatory, and pro-apoptotic proteins but also proteins of other functional categories. The number of IRF-5- and IRF-7-modulated genes was significantly higher in infected than in uninfected cells, and the transcription signature was predominantly positive. Although IRF-5 and IRF-7 stimulated a large number of common genes, a distinct functional profile was associated with each of these IRFs. The noted difference was a broad antiviral and early inflammatory transcriptional profile in infected BJAB/IRF-5 cells, whereas the IRF-7-induced transcripts were enriched for the group of mitochondrial genes and genes affecting the DNA structure. Taken together, these data indicate that IRF-5 and IRF-7 act primarily as transcriptional activators and that IRF-5-and IRF-7-induced innate antiviral response results in a broad alteration of the transcriptional profile of cellular genes.

Received for publication, January 22, 2004 , and in revised form, August 11, 2004.

^* This work was supported in part by National Institutes of Health Grants R01CA 19737-19A1, AI054537-01 (to P. M. P.), and P30 AR48310 (to L. B.) and a Flight Attendants Medical Research Institute young clinical scientist award (to B. J. B.). 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.

Both authors contributed equally to this work.

^|| Supported by National Institutes of Health Training Grant T32 CA88784.

To whom correspondence should be addressed: Cancer Research Bldg., 1650 Orleans St., Baltimore, MD 21231-1000. Tel.: 410-955-8900; Fax: 410-955-0840; E-mail: parowe{at}jhmi.edu.

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