Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis
Craig E. Daniels, … , Andrew H. Limper, Edward B. Leof
Craig E. Daniels, … , Andrew H. Limper, Edward B. Leof
Published November 1, 2004
Citation Information: J Clin Invest. 2004;114(9):1308-1316. https://doi.org/10.1172/JCI19603.
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Article Nephrology

Imatinib mesylate inhibits the profibrogenic activity of TGF-β and prevents bleomycin-mediated lung fibrosis

Abstract

Idiopathic pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Prior efforts to treat idiopathic pulmonary fibrosis that focused on anti-inflammatory therapy have not proven to be effective. Recent insight suggests that the pathogenesis is mediated through foci of dysregulated fibroblasts driven by profibrotic cytokine signaling. TGF-β and PDGF are 2 of the most potent of these cytokines. In the current study, we investigated the role of TGF-β–induced fibrosis mediated by activation of the Abelson (Abl) tyrosine kinase. Our data indicate that fibroblasts respond to TGF-β by stimulating c-Abl kinase activity independently of Smad2/3 phosphorylation or PDGFR activation. Moreover, inhibition of c-Abl by imatinib prevented TGF-β–induced ECM gene expression, morphologic transformation, and cell proliferation independently of any effect on Smad signaling. Further, using a mouse model of bleomycin-induced pulmonary fibrosis, we found a significant inhibition of lung fibrosis by imatinib. Thus, Abl family members represent common targets for the modulation of profibrotic cytokine signaling.

Authors

Craig E. Daniels, Mark C. Wilkes, Maryanne Edens, Ted J. Kottom, Stephen J. Murphy, Andrew H. Limper, Edward B. Leof

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Figure 1

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TGF-β2 stimulates c-Abl kinase activity. (A) NIH-3T3 fibroblasts were gr...
TGF-β2 stimulates c-Abl kinase activity. (A) NIH-3T3 fibroblasts were grown to confluence, placed in 0.1% FBS DMEM overnight, and stimulated with 10 ng/ml TGF-β2 or 25 ng/ml PDGF-AB for the indicated times. Parallel plates were pretreated for 20 minutes with 10 μg/ml imatinib prior to growth factor addition. Following c-Abl immunoprecipitation, in vitro kinase activity was determined as described in Methods. Similar results were obtained with AKR-2B fibroblasts and TGF-β1 (data not shown). Lower half: Prior to immunoprecipitation and kinase assay, 100 μg of protein was used for c-Abl Western analysis. (B) NIH-3T3 cells, Abl–/–Arg–/– MEFs, or Abl–/–Arg–/– fibroblasts stably expressing (+) WT-c-Abl or dominant negative c-Abl (DN-c-Abl) were plated at 2.0 106 cells per 100-mm plate and grown overnight in 20% FBS DMEM. The medium was changed to 0.5% FBS DMEM for 24 hours, and the cultures were left untreated (–) or stimulated (+) with 10 ng/ml TGF-β2 for 30 minutes. Parallel plates were pretreated for 20 minutes with 10 μg/ml imatinib prior to growth factor addition. c-Abl kinase activity (top) and Western analysis (bottom) were determined as in A.