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J. Biol. Chem., Vol. 279, Issue 8, 7339-7345, February 20, 2004

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STAT4 Is Required for Interleukin-12-induced Chromatin Remodeling of the CD25 Locus^*

Audrey O'Sullivan, Hua-Chen Chang, Qing Yu, and Mark H. Kaplan

From the Department of Microbiology and Immunology and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202 and the Walther Cancer Institute, Indianapolis, Indiana 46208

Signal transducer and activator of transcription 4 (STAT4) is a critical mediator of interleukin-12 (IL-12)-stimulated inflammatory immune responses. Despite extensive analysis of the immune responses of STAT4-deficient mice, there is still very little understood about STAT4-dependent gene induction. IL-12 stimulated increases in IL-2 receptor chain gene (CD25) mRNA levels and surface expression require STAT4. In this report, we utilize chromatin immunoprecipitation assays to analyze IL-12-stimulated and STAT4-dependent changes in chromatin remodeling of the CD25 gene. Gene activation requires binding of STAT4 to the PRRIII upstream regulatory element, the recruitment of the CREB-binding protein (CBP), and chromatin remodeling including increased acetylation and decreased methylation of histones within the CD25 promoter. Evidence suggests that STAT4 also facilitates binding of other factors to the CD25 promoter including c-Jun. Thus, these results provide a model for STAT4-dependent gene induction and a mechanism for cytokine-induced expression of the CD25 gene.

Received for publication, September 8, 2003 , and in revised form, November 17, 2003.

^* This work was supported in part by National Institutes of Health Grant AI45515 and the Indiana Genomics Initiative of Indiana University, which is supported in part by the Lilly Endowment. 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.

Supported by National Institutes of Health Training Grant T32DK007519.

To whom correspondence should be addressed: Dept. of Microbiology and Immunology, Walther Oncology Center, 950 West Walnut St., Rm. 302, Indiana University School of Medicine, Indianapolis, IN 46202. Tel.: 317-278-3696; Fax: 317-274-7592; E-mail: mkaplan2{at}iupui.edu.

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