Role of dual-specificity protein phosphatase DUSP10/MKP-5 in pulmonary fibrosis.
Am J Physiol Lung Cell Mol Physiol
; 317(5): L678-L689, 2019 11 01.
Article
em En
| MEDLINE
| ID: mdl-31483681
ABSTRACT
Mitogen-activated protein kinase (MAPK) phosphatase 5 (MKP-5) is a member of the dual-specificity family of protein tyrosine phosphatases that negatively regulates p38 MAPK and the JNK. MKP-5-deficient mice exhibit improved muscle repair and reduced fibrosis in an animal model of muscular dystrophy. Here, we asked whether the effects of MKP-5 on muscle fibrosis extend to other tissues. Using a bleomycin-induced model of pulmonary fibrosis, we found that MKP-5-deficient mice were protected from the development of lung fibrosis, expressed reduced levels of hydroxyproline and fibrogenic genes, and displayed marked polarization towards an M1-macrophage phenotype. We showed that the profibrogenic effects of the transforming growth factor-ß1 (TGF-ß1) were inhibited in MKP-5-deficient lung fibroblasts. MKP-5-deficient fibroblasts exhibited enhanced p38 MAPK activity, impaired Smad3 phosphorylation, increased Smad7 levels, and decreased expression of fibrogenic genes. Myofibroblast differentiation was attenuated in MKP-5-deficient fibroblasts. Finally, we found that MKP-5 expression was increased in idiopathic pulmonary fibrosis (IPF)-derived lung fibroblasts but not in whole IPF lungs. These data suggest that MKP-5 plays an essential role in promoting lung fibrosis. Our results couple MKP-5 with the TGF-ß1 signaling machinery and imply that MKP-5 inhibition may serve as a therapeutic target for human lung fibrosis.
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MEDLINE
Assunto principal:
Fibrose Pulmonar
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Fator de Crescimento Transformador beta1
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Fosfatases da Proteína Quinase Ativada por Mitógeno
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Fosfatases de Especificidade Dupla
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Fibroblastos
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article