Abstract
We examined the mechanism by which PGE2suppresses the expression of TNF-α in human macrophages and synovial fibroblasts. Prostaglandin E2increased, in a time and dose-dependent (EC5075±15ng/ml, mean±SD) fashion, the expression and synthesis of Egr-1/Krox24 as judged by Northern blotting and electrophoretic mobility gel-shift analysis, respectively. In human macrophagic THP-1 cells, rhIL-17 increased promoter activity by 7.6±0.35-fold over controls, an effect that was abrogated in a dose-dependent fashion by coincubations with PGE2(IC5025±4ng/ml). An intact Egr-1/Krox-24 enhancer sequence in the TNF-α promoter region was essential for the latter PGE2-dependent inhibitory effect as double base substitutions (GC→TT) in the sequence curtailed promoter response to PGE2. Overexpression of two dominant negative Egr-1/Krox-24 constructs in THP-1 cells considerably diminished the inhibitory effects of PGE2on rhIL-17-induced TNF-α mRNA expression. We conclude that PGE2inhibits induced TNF-α expression in target cells through an Egr-1/Krox-24 mediated signaling process.
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