Role of Mitogen activated-kinase (MAPK)-phosphatase (MKP)-5 in pulmonary fibrosis.

Mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5), is a member of the dual-specificity family of protein tyrosine phosphatases, which negatively regulates p38 MAPK and the c-Jun NH₂ kinase (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 extends 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 and expressed reduced levels of hydroxyproline and fibrogenic genes and a marked polarization towards an M1- macrophage phenotype. We show that the pro-fibrogenic effects of the transforming growth factor-beta1 (TGF-b1) are 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-b1 signaling machinery and imply that MKP-5 inhibition may serve as a therapeutic target for human lung fibrosis.