Inhibition by glucocorticoids of the interleukin-1beta-enhanced expression of the mast cell growth factor SCF.
1. Stem cell factor (SCF) is a major mast cell growth factor that promotes differentiation and chemotaxis of mast cells and inhibits their apoptosis. 2. We evaluated the effect of interleukin (IL)-1beta, a major pro-inflammatory cytokine, on the constitutive expression of SCF and studied the effects of two glucocorticoids, budesonide and dexamethasone, on the IL-1beta-enhanced SCF expression. 3. Human lung fibroblasts in culture were serum-starved for 48 h and treated with IL-1beta, budesonide and/or RU486. SCF cDNA was quantified after total RNA reverse transcription by on-line fluorescent polymerase chain reaction. SCF protein was quantified by ELISA. 4. IL-1beta induced an increase in SCF mRNA (+91% at 2.5 h) and protein production (+32%) by human lung fibroblasts in culture (P<0.001). 5. Budesonide inhibited IL-1beta-induced SCF mRNA expression (-68%) at 2.5 h and even more so at 10 h (-192%) (P<0.001). The expression of SCF protein also decreased by 3.5-fold at 10 h. Results were similar with dexamethasone. The glucocorticoid antagonist RU486 cancelled the effects induced by the glucocorticoids. 6. Increased SCF mRNA levels were associated with increased stability of this mRNA as measured after treatment with actinomycin D (1.9-fold at 2.5 h). Budesonide decreased this IL-1beta-enhanced stability by about 1.5-fold (P<0.001). 7. We conclude that in 'inflammatory' conditions, mimicked in vitro by IL-1beta, glucocorticoid treatment inhibits expression of the mast cell growth factor SCF. The reduced number and activation of mast cells observed in the bronchi of asthmatic patients treated by glucocorticoids may be due in part to this effect.
Da Silva
Carla Alexandra
CA
INSERM U425, Université Louis Pasteur Strasbourg I, 67401 Illkirch cedex, France. carla.dasilva@pharma.u-strasbg.fr
Kassel
Olivier
O
Mathieu
Eric
E
Massard
Gilbert
G
Gasser
Bernard
B
Frossard
Nelly
N
D000287:Administration, Topical; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D019819:Budesonide / Q000494:pharmacology; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology*; D004347:Drug Interactions; D015870:Gene Expression / Q000187:drug effects*; D005938:Glucocorticoids; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D015735:Mifepristone / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D019089:Stem Cell Factor / Q000096:biosynthesis* / Q000235:genetics
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D007375:Interleukin-1; D012333:RNA, Messenger; D019089:Stem Cell Factor; D015735:Mifepristone; D019819:Budesonide; D003907:Dexamethasone