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J. Biol. Chem., Vol. 279, Issue 18, 18451-18456, April 30, 2004

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Activation and Repression of Interleukin-12 p40 Transcription by Erythroid Kruppel-like Factor in Macrophages^*

Qi Luo, Xiaojing Ma, Sharon M. Wahl¶, James J. Bieker||, Merlin Crossley**, and Luis J. Montaner

From the The Wistar Institute, Philadelphia, Pennsylvania 19104, Department of Microbiology and Immunology, Weill Medical College, Cornell University, New York, New York 10012, ^¶Cellular Immunology Section, National Institutes of Health, Bethesda, Maryland 20892, ^||Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine, New York, New York 10029, and ^**Department of Biochemistry, The University of Sydney, Sydney, New South Wales 2006, Australia

Transcription of interleukin (IL)-12 p40 in myeloid cells is attributed to the recruitment of multiple activated transcription factors such as nuclear factor B (NFB), CCAAT enhancer-binding protein , ets-2, PU.1, and so forth. We now provide the first description of the human erythroid Kruppel-like factor (EKLF) in human primary macrophages and identify the role of EKLF in IL-12 p40 expression. EKLF-specific binding to the CACCC element (-224 to -220) on the human IL-12 p40 promoter was observed in resting human primary macrophages. Functional analysis of the CACCC element revealed a dependent role for EKLF binding in activating IL-12 p40 transcription in resting RAW264.7 cells, whereas EKLF overexpression in the presence or absence of this element repressed IL-12 p40 transcription in interferon /lipopolysaccharide-stimulated RAW264.7 cells. Murine endogenous IL-12 p40 mRNA was consistently induced by overexpressed EKLF in resting RAW264.7 cells, whereas EKLF suppressed IL-12 p40 expression in activated RAW264.7 cells. Modulation of nuclear binding activities at the IL-12 p40 NFB half-site was induced by EKLF for down-regulation of IL-12 p40 transcription in activated RAW264.7 cells, but no effect of EKLF on NFB activity was observed in resting RAW264.7 cells. Taken together, we identify EKLF as a transcription factor in macrophages able to regulate IL-12 p40 transcription depending on the cellular activation status. The bifunctional control of IL-12 p40 by EKLF and its modulation of NFB support a potential function for this factor in orchestrating IL-12 p40 production in macrophages.

Received for publication, January 12, 2004 , and in revised form, February 16, 2004.

^* This work was supported by The Philadelphia Foundation (Robert I. Jacobs Fund), M. Stengel-Miller, H. S. Miller, Jr., the Commonwealth of Pennsylvania, and National Institutes of Health Grants AI47760, AI51225, AI54891, and AI34412. 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: The Wistar Institute, Philadelphia, PA 19104. Tel.: 215-898-9143; Fax: 215-573-9272; E-mail: montaner{at}wistar.upenn.edu.

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