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and cyclosporine A in lung fibroblasts
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520-8023, USA; and
* Department of Research and Internal Medicine, University Hospital, 4031 Basel, Switzerland
1Correspondence: Yale University School of Medicine, Department of Pathology, 310 Cedar St. LB20, New Haven, CT 06520-8023, USA. E-mail: oliver.eickelberg{at}yale.edu
Lung fibrosis is a fatal condition of excess extracellular matrix (ECM)
deposition associated with increased transforming growth factor ß
(TGF-ß) activity. Although much is known about its pathological
features, our understanding of the signal transduction pathways
resulting in increased ECM and collagen deposition in response to
TGF-ß is still incompletely defined. We have previously reported that
a JunD homodimer of the transcription factor AP-1 is specifically
activated by TGF-ß in lung fibroblasts. Here we demonstrate that JunD
is also specifically required for TGF-ß-induced effects. Antisense
against JunD, but not c-fos or c-jun, significantly inhibited collagen
deposition in response to TGF-ß in primary human lung fibroblasts. We
then investigated the ability of pharmacological agents to inhibit
TGF-ß-induced signaling and collagen deposition. Cs-A and IFN-
,
but not glucocorticoids, cyclophosphamide, or azathioprine, inhibited
TGF-ß-induced signaling, as assessed by luciferase reporter gene
assays, and collagen deposition. TGF-ß antagonism by Cs-A was
associated with direct inhibition of JunD activation, as demonstrated
by electrophoretic mobility shift analyses. In contrast, the effects of
IFN- required signal transducer and activator of transcription
(STAT)-1. We thus identify the JunD isoform of AP-1 as an essential
mediator of TGF-ß-induced effects in lung fibroblasts.
TGF-ß-induced signaling and collagen deposition are efficiently
antagonized by Cs-A and IFN- treatment, both of which exhibit
distinct molecular mechanisms of action. These observations therefore
offer novel targets for future therapy of fibrotic lung
disease.—Eickelberg, O., Pansky, A., Koehler, E., Bihl, M., Tamm, M.,
Hildebrand, P., Perruchoud, A. P., Kashgarian, M., Roth, M.
Molecular mechanisms of TGF-ß antagonism by interferon and
cyclosporine A in lung fibroblasts.
Key Words: lung fibrosis • tumor growth factor ß • AP-1 • IFN- • Cs-A
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