Molecular mechanisms of TGF-beta antagonism by interferon gamma and cyclosporine A in lung fibroblasts

Lung fibrosis is a fatal condition of excess extracellular matrix (ECM) dep osition associated with increased transforming growth factor beta (TGF-beta ) activity. Although much is known about its pathological features, our und erstanding of the signal transduction pathways resulting in increased ECM a nd collagen deposition in response to TGF-beta is still incompletely define d. We have previously reported that a JunD homodimer of the transcription f actor AP-1 is specifically activated by TGF-beta in lung fibroblasts. Here we demonstrate that JunD is also specifically required for TGF-beta -induce d effects. Antisense against JunD, but not c-fos or c-jun, significantly in hibited collagen deposition in response to TGF-beta in primary human lung f ibroblasts. We then investigated the ability of pharmacological agents to i nhibit TGF-beta -induced signaling and collagen deposition. Cs-A and IFN-ga mma, but not glucocorticoids, cyclophosphamide, or azathioprine, inhibited TGF-beta -induced signaling, as assessed by luciferase reporter gene assays , and collagen deposition. TGF-beta antagonism by Cs-A was associated with direct inhibition of JunD activation, as demonstrated by electrophoretic mo bility shift analyses. In contrast, the effects of IFN-gamma required signa l transducer and activator of transcription (STAT)-1. We thus identify the JunD isoform of AP-1 as an essential mediator of TGF-beta -induced effects in lung fibroblasts. TGF-beta -induced signaling and collagen deposition ar e efficiently antagonized by Cs-A and IFN-gamma treatment, both of which ex hibit distinct molecular mechanisms of action. These observations therefore offer novel targets for future therapy of fibrotic lung disease.