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

Local production of macrophage inflammatory protein-1 beta (MIP-1 beta), a beta-chemokine that blocks human immunodeficiency virus type I (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-1 beta expression in T cells, however, are not well understood. Our results suggest that MIP-1 beta 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-1 beta promoter identified an activated protein-1 (AP-I)/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 endogenons ICER with the cAMP agonists forskolin and prostaglandin E-2 resulted in the formation of ICER-containing complexes, including an ICER:CREB heterodimer to the AP-1/CRE-like site and inhibition of MIP-1 beta promoter activity. Our data characterize an important binding site for the dominant-negative regulator ICER in the MIP-1 beta promoter and suggest that dynamic changes in the relative levels of ICER and CREB play a crucial role in cAMP-mediated attenuation of MIP-1 beta transcription in human T cells. J. Leukoc. Biol. 79: 378-387; 2006.