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J. Biol. Chem., Vol. 280, Issue 26, 24347-24355, July 1, 2005

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Interferon Regulatory Factor 1 Is an Essential and Direct Transcriptional Activator for Interferon -induced RANTES/CCl5 Expression in Macrophages^*

Jianguo Liu, Xiuqin Guan, and Xiaojing Ma

From the Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021

Interferon regulatory factor 1 (IRF-1) is an important transcription factor in interferon (IFN)-mediated signaling in the development and function of NK cells and cytotoxic T lymphocytes. RANTES (regulated on activation normal T cell expressed and secreted; CCL5) is a member of the CC chemokine family of proteins, which is strongly chemoattractant for several important immune cell types in host defense against infectious agents and cancer. However, the role of IFN and IRF-1 in the regulation of RANTES gene expression and their operative mechanisms in macrophages have not been established. We report here that RANTES expression in IRF-1-null mice, primarily in macrophages, in response to carcinogenic stimulation in vivo and in vitro and to IFN but not to lipopolysaccharide in vitro, was markedly decreased. As a result, RANTES-mediated chemoattraction of CCR5⁺ target cells was also severely impaired. Adenovirus-mediated gene transduction of IRF-1 in primary macrophages resulted in enhanced RANTES expression. The IFN and IRF1 response element was localized to a TTTTC motif at –147 to –143 of the mouse RANTES promoter, to which endogenous or recombinant IRF-1 can physically bind in vitro and in vivo. This study uncovers a novel IFN-induced pathway in RANTES expression mediated by IRF-1 in macrophages and elucidates an important host defense mechanism against neoplastic transformation.

Received for publication, January 26, 2005 , and in revised form, April 21, 2005.

^* 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.

To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Ave., New York, NY 10021. Tel.: 212-746-4404; Fax: 212-746-4427; E-mail: xim2002{at}med.cornell.edu.

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