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 2

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TGF-β2 activation of c-Abl is independent of PDGFR signaling. (A) NIH-3T...
TGF-β2 activation of c-Abl is independent of PDGFR signaling. (A) NIH-3T3 cells were treated for the indicated times with TGF-β2 (10 ng/ml) or PDGF-AB (25 ng/ml). Cell lysates were prepared and processed for c-Abl kinase activity (first panel), total c-Abl protein (second panel), tyrosine-phosphorylated PDGF-β receptor (p-PDGFR; third panel), or total PDGF-β receptor (fourth panel) as described in Methods. (B) NIH-3T3 cells were treated as described in Figure 1. PDGF-α and -β receptor–null F cells were seeded at 1.5 × 106 cells per 100-mm dish. Following overnight growth, the medium was replaced with serum-free DMEM alone (PDGFR–/–) or adenovirus (MOI 100) expressing the type I and type II TGF-β receptors (Ad.TGF-βRI and Ad.TGF-βRII, respectively) for 24 hours. Cultures were left untreated (–) or stimulated (+) with 10 ng/ml TGF-β2 for 30 minutes and processed for c-Abl kinase activity (first panel), or total c-Abl (second panel), PDGF-β receptor (third panel), type I TGF-β receptor (TGF-βRI; fourth panel), or type II TGF-β receptor (TGF-βRII; fifth panel) protein.