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J. Biol. Chem., Vol. 278, Issue 41, 39372-39382, October 10, 2003

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Activation of the Murine Interleukin-12 p40 Promoter by Functional Interactions between NFAT and ICSBP^*

Chen Zhu , Kavitha Rao , Huabao Xiong , Khatuna Gagnidze , Fengling Li , Curt Horvath  and Scott Plevy  ¶

From the Immunobiology Center, Mount Sinai School of Medicine, New York, New York 10029 and the Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261

Interleukin (IL)-12 is a heterodimeric cytokine that is critical for the development of a T-helper-1 immune response and immunity against intracellular pathogens. The IL-12 p40 gene product, expressed specifically in macrophages and dendritic cells, heterodimerizes with p35 to form bioactive IL-12, and heterodimerizes with p19 to comprise the cytokine IL-23. Regulation of the murine IL-12 p40 promoter is complex. Multiple cis-acting elements have been characterized that are involved in activation by bacterial products. However, molecular mechanisms through which interferon (IFN)- and bacterial products synergistically activate IL-12 p40 gene expression are less clear. In this study, a composite NFAT/ICSBP binding site at –68 to –54 is identified that is functionally important for p40 promoter activation by lipopolysaccharide (LPS) and LPS plus IFN-. DNA binding of NFAT and ICSBP is demonstrated on the endogenous promoter by chromatin immunoprecipitation. NFAT is required for ICSBP binding to this region. Overexpression of NFAT and ICSBP synergistically activates the p40 promoter. A dominant negative NFAT molecule attenuates LPS- and IFN--activated endogenous IL-12 p40 mRNA expression. A physical association between NFAT and ICSBP in the absence of DNA is detected by co-immunoprecipitation of endogenous proteins. Three NFAT domains are required for ICSBP interaction. Finally, in LPS- and IFN--activated RAW-264.7 cells, the association between NFAT and ICSBP is abrogated by IL-10 priming.

Received for publication, June 18, 2003

^* 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 all correspondence should be addressed: Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh School of Medicine, Scaife Hall, Rm. S857, 3550 Terrace St., Pittsburgh, PA 15261. Tel.: 412-648-9573; Fax: 412-648-9731; E-mail: sep1{at}pitt.edu.

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