Glucocorticoids inhibit the transcriptional induction of JE, a platelet-derived growth factor-inducible gene.
Macrophages and monocytes have essential roles in normal wound healing, in the immune response, and in the pathogenesis of atherosclerosis. Platelet-derived growth factor (PDGF) stimulates the transcription of the early response gene, JE, and its human homolog, macrophage chemotactic protein-1 (MCP-1) in fibroblasts. JE/MCP-1 encodes a cytokine which is a member of a superfamily of small inducible genes that include platelet factor 4, beta-thromboglobulin, 310-C/NAP-1/IL-8, IP-10, KC/gro/MGSA, and others which may play important roles in the inflammatory and immune response. We now report that glucocorticoids inhibit the transcriptional induction of the JE gene by PDGF and serum in a dose-dependent manner. The glucocorticoid response followed the expected anti-inflammatory rank order of potency and was not due to a shift in the time course of induction. Nonsteroidal anti-inflammatory agents were ineffective in reducing JE mRNA levels. Dexamethasone inhibited the accumulation of JE transcripts induced by PDGF, 12-O-tetradecanoylphorbol-13-acetate, and double-stranded synthetic RNA. Nuclear runoff assays demonstrated that the negative regulation occurred by decreasing the transcriptional induction of the JE gene. No effects on JE message stability could be detected in the presence of dexamethasone. The protein synthesis inhibitors cycloheximide and puromycin reversed the glucocorticoid-mediated inhibition and suggested that new protein synthesis was necessary. These results suggest that the transcriptional inhibition of glucocorticoids is mediated by the expression of a labile transcriptional repressor for the JE gene.
Kawahara
R S
RS
Department of Medicine, Jewish Hospital, Washington University Medical Center, St. Louis, Missouri 63110.
Deng
Z W
ZW
Deuel
T F
TF
D000818:Animals; D015152:Blotting, Northern; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology; D003470:Culture Media; D016207:Cytokines / Q000235:genetics*; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005796:Genes / Q000187:drug effects*; D008775:Methylprednisolone / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
D003470:Culture Media; D016207:Cytokines; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011994:Recombinant Proteins; D012313:RNA; D003907:Dexamethasone; D008775:Methylprednisolone