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 cel ls produced modest amounts of IL-11, and transforming growth factor (TGF)-b eta 1 was a potent, dose-dependent stimulator of A549 cell IL-11 elaboratio n. Dexamethasone inhibited the levels of basal and TGF-beta 1-stimulated IL -11 elaboration in a dose-dependent fashion. In the setting of TGF-beta 1 s timulation, dexamethasone caused a >90% decrease in IL-11 production at 10( -6) M, a 50% decrease in IL-11 production at similar to 1 x 10(-9) M, and s ignificant inhibition at 10(-10) M. This dexamethasone-induced inhibition w as reversed by the glucocorticoid-receptor antagonist RU-486. Dexamethasone also inhibited respiratory syncytial virus, rhinovirus, and TGF-beta 1-sti mulated IL-11 production by MRC-5 lung fibroblasts. In all cases, dexametha sone caused comparable changes in IL-11 mRNA accumulation. Nuclear run-on s tudies demonstrated that dexamethasone caused a modest (less than or equal to 40%) decrease in TGF-beta 1-stimulated IL-11 gene transcription Actinomy cin D pulse-chase experiments demonstrated that dexamethasone simultaneousl y destabilized IL-11 mRNA. Dexamethasone also inhibited TGF-beta 1-stimulat ed IL-11 promoter-driven luciferase activity but did not diminish activator protein-1 binding to IL-11 promoter sequences. Glucocorticoids inhibit lun g cell IL-11 production via a complex mechanism that involves the inhibitio n of IL-11 gene transcription and the destabilization of IL-11 mRNA.