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(Journal of Leukocyte Biology. 2006;79:378-387.)
© 2006 by Society for Leukocyte Biology

Suppression of MIP-1ß transcription in human T cells is regulated by inducible cAMP early repressor (ICER)

Oxana Barabitskaja^*, James S. Foulke, Jr.^*, Shibani Pati^*, Josef Bodor and Marvin S. Reitz, Jr.^*,,1

^* Institute of Human Virology, University of Maryland Biotechnology Institute, and
Department of Microbiology and Immunology, University of Maryland, Baltimore;
Department of Pathology, Columbia University, New York, New York

¹ Correspondence: Institute of Human Virology, University of Maryland, 725 W. Lombard St., Baltimore, MD 21201. E-mail: reitz{at}umbi.umd.edu

Local production of macrophage inflammatory protein-1ß (MIP-1ß), a ß-chemokine that blocks human immunodeficiency virus type 1 (HIV-1) entry into CD4+ CC chemokine receptor 5+ target cells, may be a significant factor in resistance to HIV-1 infection and control of local viral spread. The mechanisms governing MIP-1ß expression in T cells, however, are not well understood. Our results suggest that MIP-1ß RNA expression in T cells is dynamically regulated by transcriptional factors of the cyclic adenosine monophosphate (cAMP) responsive element (CRE)-binding (CREB)/modulator family. Transient transfection of primary human T cells with 5' deletion and site-specific mutants of the human MIP-1ß promoter identified an activated protein-1 (AP-1)/CRE-like motif at position –74 to –65 base pairs, relative to the TATA box as a vital cis-acting element and a binding site for inducible cAMP early repressor (ICER). Ectopic expression of ICER or induction of endogenous ICER with the cAMP agonists forskolin and prostaglandin E₂ resulted in the formation of ICER-containing complexes, including an ICER:CREB heterodimer to the AP-1/CRE-like site and inhibition of MIP-1ß promoter activity. Our data characterize an important binding site for the dominant-negative regulator ICER in the MIP-1ß promoter and suggest that dynamic changes in the relative levels of ICER and CREB play a crucial role in cAMP-mediated attenuation of MIP-1ß transcription in human T cells.

Key Words: chemokine • promoter • CREB

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