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10.1074/jbc.M113.542407

http://scihub22266oqcxt.onion/10.1074/jbc.M113.542407
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suck abstract from ncbi


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pmid24790080
      J+Biol+Chem 2014 ; 289 (23 ): 16239-51
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  • Regulation of TGF-?1-driven differentiation of human lung fibroblasts: emerging roles of cathepsin B and cystatin C #MMPMID24790080
  • Kasabova M ; Joulin-Giet A ; Lecaille F ; Gilmore BF ; Marchand-Adam S ; Saidi A ; Lalmanach G
  • J Biol Chem 2014[Jun]; 289 (23 ): 16239-51 PMID24790080 show ga
  • Lung matrix homeostasis partly depends on the fine regulation of proteolytic activities. We examined the expression of human cysteine cathepsins (Cats) and their relative contribution to TGF-?1-induced fibroblast differentiation into myofibroblasts. Assays were conducted using both primary fibroblasts obtained from patients with idiopathic pulmonary fibrosis and human lung CCD-19Lu fibroblasts. Pharmacological inhibition and genetic silencing of Cat B diminished ?-smooth muscle actin expression, delayed fibroblast differentiation, and led to an accumulation of intracellular 50-kDa TGF-?1. Moreover, the addition of Cat B generated a 25-kDa mature form of TGF-?1 in Cat B siRNA-pretreated lysates. Inhibition of Cat B decreased Smad 2/3 phosphorylation but had no effect on p38 MAPK and JNK phosphorylation, indicating that Cat B mostly disturbs TGF-?1-driven canonical Smad signaling pathway. Although mRNA expression of cystatin C was stable, its secretion, which was inhibited by brefeldin A, increased during TGF-?1-induced differentiation of idiopathic pulmonary fibrosis and CCD-19Lu fibroblasts. In addition, cystatin C participated in the control of extracellular Cats, because its gene silencing restored their proteolytic activities. These data support the notion that Cat B participates in lung myofibrogenesis as suggested for stellate cells during liver fibrosis. Moreover, we propose that TGF-?1 promotes fibrosis by driving the effective cystatin C-dependent inhibition of extracellular matrix-degrading Cats.
  • |Blotting, Western [MESH]
  • |Cathepsin B/genetics/*physiology [MESH]
  • |Cell Differentiation/*physiology [MESH]
  • |Cells, Cultured [MESH]
  • |Cystatin C/*physiology [MESH]
  • |Fibroblasts/cytology [MESH]
  • |Gene Silencing [MESH]
  • |Humans [MESH]
  • |Lung/*cytology [MESH]
  • |Phosphorylation [MESH]
  • |RNA Interference [MESH]
  • |RNA, Small Interfering [MESH]
  • |Real-Time Polymerase Chain Reaction [MESH]
  • |Signal Transduction [MESH]
  • |Smad Proteins/metabolism [MESH]


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