Dexamethasone regulation of lung epithelial cell and fibroblast interleukin-11 production.
Studies were undertaken to define the effects of corticosteroids on stromal cell interleukin (IL)-11 production. Unstimulated A549 epithelial-like cells produced modest amounts of IL-11, and transforming growth factor (TGF)-beta1 was a potent, dose-dependent stimulator of A549 cell IL-11 elaboration. Dexamethasone inhibited the levels of basal and TGF-beta1-stimulated IL-11 elaboration in a dose-dependent fashion. In the setting of TGF-beta1 stimulation, dexamethasone caused a >90% decrease in IL-11 production at 10(-6) M, a 50% decrease in IL-11 production at approximately 1 x 10(-9) M, and significant inhibition at 10(-10) M. This dexamethasone-induced inhibition was reversed by the glucocorticoid-receptor antagonist RU-486. Dexamethasone also inhibited respiratory syncytial virus, rhinovirus, and TGF-beta1-stimulated IL-11 production by MRC-5 lung fibroblasts. In all cases, dexamethasone caused comparable changes in IL-11 mRNA accumulation. Nuclear run-on studies demonstrated that dexamethasone caused a modest (</=40%) decrease in TGF-beta1-stimulated IL-11 gene transcription. Actinomycin D pulse-chase experiments demonstrated that dexamethasone simultaneously destabilized IL-11 mRNA. Dexamethasone also inhibited TGF-beta1-stimulated IL-11 promoter-driven luciferase activity but did not diminish activator protein-1 binding to IL-11 promoter sequences. Glucocorticoids inhibit lung cell IL-11 production via a complex mechanism that involves the inhibition of IL-11 gene transcription and the destabilization of IL-11 mRNA.
Wang
J
J
Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8057, USA.
Zhu
Z
Z
Nolfo
R
R
Elias
J A
JA
D016923:Cell Death / Q000502:physiology; D003907:Dexamethasone / Q000494:pharmacology*; D004355:Drug Stability; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005347:Fibroblasts / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D017370:Interleukin-11 / Q000096:biosynthesis* / Q000235:genetics; D008168:Lung / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D005938:Glucocorticoids; D017370:Interleukin-11; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D003907:Dexamethasone