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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 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.