pulmicort and pyrrolidine-dithiocarbamic-acid

Expression of stem cell factor SCF, a major mast cell growth factor, is potentiated shortly after co-treatment with interleukin (IL)-1beta and glucocorticoids. SCF promoter contains a GRE-like sequence and a putative kappaB site. We assessed the mechanisms of the regulation of SCF transcription in human lung fibroblasts in culture. Chromatin immunoprecipitation showed that co-treatment with IL-1beta and the glucocorticoid budesonide increased the SCF promoter occupancy by NF-kappaB and GR, as compared with IL-1beta and budesonide alone. In reporter gene assays, IL-1beta time-dependently increased the promoter activity, which was abolished by either pre-treatment with the MAP kinase inhibitors PD98059 (MEK) and SB203580 (p38), pre-treatment with the NF-kappaB inhibitor PDTC, or deletion of the kappaB site. Budesonide time-dependently decreased the promoter activity, an effect requiring the GRE-like element. Co-treatment with IL-1beta and budesonide potentiated the promoter activity at 30 min, an effect blocked by PD98059 and SB203580, PDTC, or deletion of the kappaB or GRE-like element. In conclusion, the GRE-like sequence mediating the repression of SCF expression, thus acting as a negative-responsive element, is turned into a positive element in an NF-kappaB site-dependent manner, indicating a concerted action of these two regulatory elements in the potentiation of SCF gene expression.

Topics: Budesonide; Cells, Cultured; Drug Synergism; Enzyme Inhibitors; Fibroblasts; Glucocorticoids; Humans; Interleukin-1; Mifepristone; Mitogen-Activated Protein Kinases; Models, Genetic; NF-kappa B; Promoter Regions, Genetic; Pyrrolidines; Receptors, Glucocorticoid; Response Elements; Stem Cell Factor; Thiocarbamates; Transcriptional Activation