HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 21, 14295-14308, May 23, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/21/14295    most recent M800501200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paun, A. Articles by Pitha, P. M. Search for Related Content PubMed PubMed Citation Articles by Paun, A. Articles by Pitha, P. M. Social Bookmarking                      What's this?

Functional Characterization of Murine Interferon Regulatory Factor 5 (IRF-5) and Its Role in the Innate Antiviral Response^*

Andrea Paun, Jorgen T. Reinert¹, Zhaozhao Jiang, Carey Medin, Mumtaz Yaseen Balkhi, Katherine A. Fitzgerald², and Paula M. Pitha^¶||23

From the Sidney Kimmel Comprehensive Cancer Center, the ^¶Department of Molecular Biology and Genetics and ^||Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21231 and the Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts

Although the role of human IRF-5 in antiviral and inflammatory responses in vitro has been well characterized, much remains to be elucidated about murine IRF-5. Murine IRF-5, unlike the heavily spliced human gene, is primarily expressed as a full-length transcript, with only a single splice variant that was detected in very low levels in the bone marrow of C57BL/6J mice. This bone marrow variant contains a 288-nucleotide deletion from exons 4–6 and exhibits impaired transcriptional activity. The murine IRF-5 can be activated by both TBK1 and MyD88 to form homodimers and bind to and activate transcription of type I interferon and inflammatory cytokine genes. The importance of IRF-5 in the antiviral and inflammatory response in vivo is highlighted by marked reductions in serum levels of type I interferon and tumor necrosis factor (TNF) in Newcastle disease virus-infected Irf5^–/– mice. IRF-5 is critical for TLR3-, TLR4-, and TLR9-dependent induction of TNF in CD11c⁺ dendritic cells. In contrast, TLR9, but not TLR3/4-mediated induction of type I IFN transcription, is dependent on IRF-5 in these cells. In addition, IRF-5 regulates TNF but not type I interferon gene transcription in Newcastle disease virus-infected peritoneal macrophages. Altogether, these data reveal the cell type-specific importance of IRF-5 in MyD88-mediated antiviral pathways and the widespread role of IRF-5 in the regulation of inflammatory cytokines.

Received for publication, January 18, 2008 , and in revised form, March 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 AI067632 (to P. M. P.) and AI067497 (to K. A. F.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Experimental Procedures, Table 1, and Figs. 1–4.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) EU_401974.

¹ Present address: Skejby Sygehus, Aarhus University Hospital, Aarhus, Denmark.

² Both authors contributed equally to this work.

³ To whom correspondence should be addressed: The Johns Hopkins School of Medicine, 1650 Orleans St., Baltimore, MD 21231. Tel.: 410-955-8871; Fax: 410-955-0840; E-mail: parowe{at}jhmi.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. H. Mogensen Pathogen Recognition and Inflammatory Signaling in Innate Immune Defenses Clin. Microbiol. Rev., April 1, 2009; 22(2): 240 - 273. [Abstract] [Full Text] [PDF]

				M. Y. Balkhi, K. A. Fitzgerald, and P. M. Pitha Functional Regulation of MyD88-Activated Interferon Regulatory Factor 5 by K63-Linked Polyubiquitination Mol. Cell. Biol., December 15, 2008; 28(24): 7296 - 7308. [Abstract] [Full Text] [PDF]