Paradoxical early glucocorticoid induction of stem cell factor (SCF) expression in inflammatory conditions.
1. Stem cell factor (SCF) is a major growth factor for mast cells, promoting their differentiation and chemotaxis. Its expression is regulated by glucocorticoids in inflammatory conditions, showing an early increased protein expression, before the expected anti-inflammatory decrease (Da Silva et al., Br. J. Pharmacol. 2002:135,1634). 2. We here evaluated the early kinetic of SCF expression regulated by interleukin (IL)-1beta, budesonide and the combination of both in human lung fibroblasts in culture. 3. Budesonide potentiated the IL-1beta-enhanced expression of SCF mRNA (+103%) and protein (+98%) very shortly after treatment (at 30 min and 1 h, respectively). A gentle downregulation followed. This potentiating effect of budesonide was related to increased SCF mRNA stability and SCF gene transcription. 4. Deletion of a kappaB-like site that we identified in the first intron of the SCF gene, in a luciferase reporter system, abolished the potentiation by budesonide, as well as the effect of IL-1beta alone, as compared to the wild-type construction activity. 5. All budesonide-induced effects were glucocorticoid-receptor dependent, since they were reproduced by dexamethasone and blocked by RU486. 6. IL-1beta+budesonide did not affect the relative expression of the soluble and membrane-bound forms of SCF. 7. In conclusion, our results clearly show that glucocorticoids act very early to adversely increase the expression of SCF mRNA and protein in the inflammatory conditions created by IL-1beta, and that this effect involves increased mRNA stability and increased gene expression through activation of the NF-kappaB-like responsive element.
Da Silva
Carla Alexandra
CA
Inserm U425, Université Louis Pasteur Strasbourg I, France. carla.dasilva@pharm.u-strasbg.fr
Kassel
Olivier
O
Lebouquin
Renaud
R
Lacroix
Emmanuel Jean
EJ
Frossard
Nelly
N
D019819:Budesonide / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D004357:Drug Synergism; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000166:cytology; D015735:Mifepristone / Q000494:pharmacology; D016328:NF-kappa B / Q000502:physiology; D010957:Plasmids / Q000187:drug effects / Q000235:genetics; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000502:physiology; D019089:Stem Cell Factor / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D023822:Tissue Engineering / Q000379:methods; D014158:Transcription, Genetic / Q000187:drug effects* / Q000235:genetics; D014162:Transfection / Q000379:methods
D018076:DNA, Complementary; D005938:Glucocorticoids; D007375:Interleukin-1; D016328:NF-kappa B; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D019089:Stem Cell Factor; D015735:Mifepristone; D019819:Budesonide