trans-retinoic acid blocks platelet-derived growth factor-BB-induced expression of the murine monocyte chemoattractant-1 gene by blocking the assembly of a promoter proximal Sp1 binding site

Proper regulation of the CC chemokine MCP-1 (monocyte chemoattractant prote in-1) is important for normal inflammatory responses. MCP-1 is regulated by a wide variety of agents, including platelet-derived growth factor-BB (PDG F-BB) and tumor necrosis factor-alpha (TNF). Using both in vivo and in vitr o assays, the elements required for expression between these two cytokines were compared. In vivo genomic footprinting showed that PDGF-BB induction o ccurred through the occupancy of the proximal regulatory region, and unlike TNF induction, no changes in the NF-kappa B binding, distal regulatory reg ion occurred. Treatment of cells with trans-retinoic acid, an inhibitor of PDGF-BB activity, resulted in a 50% reduction in PDGF-BB-mediated induction and a concomitant block in the assembly of the proximal regulatory region. trans-Retinoic acid had minimal effect on TNF induction or promoter occupa ncy. An inhibitor of histone deacetylation was found to stimulate expressio n of MCP-1 in a manner that correlated with increased accessibility to the proximal regulatory region, These results show that the mechanisms of PDGF- BB and TNF activation of MCP-1 are distinct, although they both require the proximal regulatory region Sp1 binding site. The results also suggest that part of the mechanism used by both of these cytokines involves a process t hat regulates transcription factor access to the regulatory regions.