Glucocorticoids promote TGF‐beta signaling in lung fibroblasts by upregulating ligand and receptor expression, and uncoupling negative‐feedback inhibition

Glucocorticoids are used to treat inflammatory lung diseases, in which dysregulated transforming growth factor (TGF)‐beta signaling is implicated. We hypothesized that glucocorticoid and TGF‐beta pathways interact. The mRNA levels of the serpine1 gene, which served as readout of TGF‐beta signaling, were elevated 2.8‐fold by dexamethasone (DEX; 20 nM), 5.7‐fold by TGF‐beta and 32‐fold by TGF‐beta after DEX treatment (18 h), suggesting pathway synergism. Parallel trends were observed using the ctgf gene as readout, in primary lung fibroblasts, and in lungs from DEX‐treated mice. In the presence of a TGF‐beta signaling inhibitor (SB431542), DEX upregulated TGF‐beta2 mRNA (8.2‐fold; p=0.0007) and protein (10‐fold, by ELISA) expression, and betaglycan (a TGF‐beta receptor) mRNA levels (2‐fold; p=0.034). DEX downregulated smad7 (2‐fold, p=0.048) and smurf1 (1.5‐fold; p=0.036) mRNA expression, representing TGF‐beta‐induced genes which direct negative‐feedback signaling. DEX suppressed TGF‐beta induction of smad7, uncoupling feedback inhibition of the TGF‐beta pathway. A pivotal role for betaglycan was revealed by siRNA knockdown. Identical trends were seen with budesonide, methylprednisolone and fluticasone. These data suggest that glucocorticoids promote TGF‐beta signaling in lung fibroblasts by upregulating ligand and receptor expression, and uncoupling negative‐feedback inhibition.