Abstract
Pulmonary fibrosis is a progressive disease characterized by a widespread accumulation of myofibroblasts and extracellular matrix components. Growing evidences support that cysteine cathepsins, embracing cathepsin B (CatB) that affects TGF-β1-driven Smad pathway, along with their extracellular inhibitor cystatin C, participate in myofibrogenesis. Here we established that curcumin, a potent antifibrotic drug used in traditional Asian medicine, impaired the expression of both α-smooth muscle actin and mature TGF-β1 and inhibited the differentiation of human lung fibroblasts (CCD-19Lu cells). Curcumin induced a compelling upregulation of CatB and CatL. Conversely cystatin C was downregulated, which allowed the recovery of the peptidase activity of secreted cathepsins and the restoration of the proteolytic balance. Consistently, the amount of both insoluble and soluble type I collagen decreased, reaching levels similar to those observed for undifferentiated fibroblasts. The signaling pathways activated by curcumin were further examined. Curcumin triggered the expression of nuclear peroxisome proliferator-activated receptor γ (PPARγ). Contrariwise PPARγ inhibition, either by an antagonist (2-chloro-5-nitro-N-4-pyridinyl-benzamide) or by RNA silencing, restored TGF-β1-driven differentiation of curcumin-treated CCD-19Lu cells. PPARγ response element (PPRE)-like sequences were identified in the promoter regions of both CatB and CatL. Finally, we established that the transcriptional induction of CatB and CatL depends on the binding of PPARγ to PPRE sequences as a PPARγ/Retinoid X Receptor-α heterodimer.
Highlights
Pulmonary fibrosis (PF), a distinctive form of chronic interstitial pneumonia[1,2,3,4], is a progressive and irreversible fibrotic disease
Fibroblasts stimulated with transforming growth factor-β1 (TGF-β1) (5 ng/ml) were further treated with curcumin (0–10 μM) during 48 h, total RNA was isolated and α-smooth muscle actin (α-SMA) expression level determined by real-time quantitative PCR (Fig. 1b)
Curcumin significantly decreased the expression of TGF-β1 mRNA, down to levels similar to those observed in undifferentiated fibroblasts (Fig. 2a)
Summary
Pulmonary fibrosis (PF), a distinctive form of chronic interstitial pneumonia[1,2,3,4], is a progressive and irreversible fibrotic disease. We observed a significant increase of cystatin C in BALFs from patients suffering from idiopathic pulmonary fibrosis, suggesting its possible use as a clinical marker of fibrosis[30] These results reflect the dysregulation of active cathepsins in lung, which in turn can promote myofibrogenesis. Brömme and coworkers observed that curcumin increases the expression of lung CatK and prevented collagen accumulation in a murine model of bleomycin-induced pulmonary fibrosis[26]. According to these seminal results, the goal of the present study was to decipher the molecular mechanisms underlying the antifibrotic properties of curcumin, using human lung CCD-19Lu fibroblasts
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