Suppression of MIP-1beta transcription in human T cells is regulated by inducible cAMP early repressor (ICER).
Local production of macrophage inflammatory protein-1beta (MIP-1beta), a beta-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-1beta expression in T cells, however, are not well understood. Our results suggest that MIP-1beta 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-1beta 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-1beta promoter activity. Our data characterize an important binding site for the dominant-negative regulator ICER in the MIP-1beta promoter and suggest that dynamic changes in the relative levels of ICER and CREB play a crucial role in cAMP-mediated attenuation of MIP-1beta transcription in human T cells.
Barabitskaja
Oxana
O
Institute of Human Virology, University of Maryland Biotechnology Institute,Baltimore, MD 21201, USA.
Foulke
James S
JS
Pati
Shibani
S
Bodor
Josef
J
Reitz
Marvin S
MS
D001483:Base Sequence; D002478:Cells, Cultured; D054407:Chemokine CCL4; D051786:Cyclic AMP Response Element Modulator / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D012313:RNA / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects*
C497410:CREM protein, human; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D011994:Recombinant Proteins; D051786:Cyclic AMP Response Element Modulator; D012313:RNA