| First Author | Xylourgidis N | Year | 2019 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 317 |
| Issue | 5 | Pages | L678-L689 |
| PubMed ID | 31483681 | Mgi Jnum | J:281660 |
| Mgi Id | MGI:6377350 | Doi | 10.1152/ajplung.00264.2018 |
| Citation | Xylourgidis N, et al. (2019) Role of dual-specificity protein phosphatase DUSP10/MKP-5 in pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 317(5):L678-L689 |
| abstractText | 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-beta1 (TGF-beta1) 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-beta1 signaling machinery and imply that MKP-5 inhibition may serve as a therapeutic target for human lung fibrosis. |
