Up- and down-regulation by glucocorticoids of the constitutive expression of the mast cell growth factor stem cell factor by human lung fibroblasts in culture.
Stem cell factor (SCF) is a major mast cell growth factor that promotes differentiation and chemotaxis of mast cells and inhibits their apoptosis. SCF therefore may be involved in diseases associated with an increased number of tissue mast cells such as asthma, for which the major treatment is glucocorticoids. In this study, we evaluated the effect of the glucocorticoid budesonide on the constitutive expression of SCF by human lung fibroblasts in primary culture. Budesonide (0.1 microM) induced a time-dependent biphasic effect on SCF mRNA and protein production. A short treatment (2.5-10 hr) induced an inhibition of SCF protein accumulation (-58% at 2.5 hr) and mRNA expression (-69% at 2.5 hr), associated with an accelerated decay of SCF mRNA and with a decrease in SCF gene transcription observed by nuclear run-on assay. Longer treatment (24-72 hr) led to increases in SCF protein accumulation (+64% at 48 hr) and mRNA expression (+125% at 24 hr) as a consequence of transcriptional activation. Similar effects of a decrease followed by an increase in SCF production were observed using another glucocorticoid, dexamethasone. Overall, our results show that glucocorticoids potently regulate SCF expression in human lung fibroblasts, successively decreasing and increasing SCF mRNA levels according to treatment duration. Such time-dependent modulation of SCF levels may explain some current discrepant findings about the effects of glucocorticoids on SCF production and may have functional consequences during glucocorticoid treatment, such as asthma therapy.
Kassel
O
O
Institut National de la Santé et de la Recherche Médicale U425, Neuroimmunopharmacologie Pulmonaire, Faculté de Pharmacie, 67401 Illkirch Cedex, France.
Schmidlin
F
F
Duvernelle
C
C
de Blay
F
F
Frossard
N
N
D019819:Budesonide / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D019089:Stem Cell Factor / Q000096:biosynthesis* / Q000235:genetics; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects
D005938:Glucocorticoids; D012333:RNA, Messenger; D019089:Stem Cell Factor; D019819:Budesonide