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J. Biol. Chem., Vol. 280, Issue 39, 33123-33131, September 30, 2005

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PU.1 Regulates the Tissue-specific Expression of Dendritic Cell-specific Intercellular Adhesion Molecule (ICAM)-3-grabbing Nonintegrin^*

From the Centro de Investigaciones Biológicas, CSIC, Madrid 28040, Spain

Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is a cell surface C-type lectin expressed on myeloid dendritic cells and certain tissue macrophages, which mediates antigen capture for processing and presentation and participates in intercellular interactions with naive T lymphocytes or endothelial cells. In their strategy to evade immunosurveillance, numerous pathogenic microorganisms, including human immunodeficiency virus and Mycobacterium, bind to DC-SIGN in order to gain access to dendritic cells. We present evidence that PU.1 dictates the basal and cell-specific activity of DC-SIGN gene-regulatory region through in vivo occupancy of two functional Ets elements, whose integrity is required for PU.1 responsiveness and for the cooperative actions of PU.1 and other transcription factors (Myb, RUNX) on the DC-SIGN gene proximal regulatory region. In addition, protein analysis and gene profiling experiments indicate that DC-SIGN and PU.1 are coordinately expressed upon classical and alternative macrophage activation and during dendritic cell maturation. Moreover, small interfering RNA-mediated reduction of PU.1 expression results in diminished DC-SIGN cellular levels. Altogether, these results indicate that PU.1 is involved in the myeloid-specific expression of DC-SIGN in myeloid cells, a contribution that can be framed within the role that PU.1 has on the acquisition of the antigen uptake molecular repertoire by dendritic cells and macrophages.

Received for publication, March 29, 2005 , and in revised form, June 13, 2005.

^* This work was supported by Ministerio de Educación y Ciencia Grant SAF2002-04615-C02-01 and Grant GEN2003-20649-C06-01/NAC and Fundación para la Investigación y Prevención del SIDA en España Grant 36422/03 (to A. L. C.) and Grant GEN2003-20649-C06-06/NAC (to M. A. V.). 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.

¹ Supported by a predoctoral grant from Ministerio de Educación y Ciencia (Spain).

² Supported by an I3P postdoctoral contract through CSIC.

³ To whom correspondence should be addressed: Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, Madrid 28040, Spain. Tel.: 34-91-8373112 (ext. 4376); Fax: 34-91-5627518; E-mail: acorbi{at}cib.csic.es.

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