Identification of a novel dexamethasone-sensitive RNA-destabilizing regionon rat monocyte chemoattractant protein 1 mRNA

Glucocorticoids are potent anti-inflammatory agents widely used in the trea tment of human disease. We have previously shown that the inflammatory cyto kine monocyte chemoattractant protein 1 (MCP-1) is regulated posttranscript ionally by glucocorticoids in arterial smooth muscle cells (SMC). To elucid ate the mechanism mediating this effect, in vitro-transcribed radiolabeled MCP-1 mRNA was incubated with cytoplasmic extracts from SMC and analyzed by gel electrophoresis. Extracts from SMC treated with platelet-derived growt h factor (PDGF) did not degrade the transcripts for up to 3 h. In contrast, extracts from cells treated with 1 mu M dexamethasone (Dex) alone or in co mbination with PDGF degraded the probe with a half-life of approximate to 1 5 min. Dex had maximal effect at concentrations above 0.01 mu M and was eff ective on both rat and human MCP-1 transcripts. By deletion analysis, the D ex-sensitive region of the MCP-1 mRNA was localized to the initial 224 nucl eotides (nt) at the 5' end and did not involve an AU-rich sequence in the 3 ' untranslated end. The 224-nt region conferred Dex sensitivity to heterolo gous mRNA. These studies provide new insights into the molecular mechanisms underlying the effect of glucocorticoids on gene expression.