Role of dual-specificity protein phosphatase DUSP10/MKP-5 in pulmonary fibrosis

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-β1 (TGF-β1) 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-β1 signaling machinery and imply that MKP-5 inhibition may serve as a therapeutic target for human lung fibrosis.

MAP Kinase Phosphatase-5 Deficiency Protects Against Pressure Overload-Induced Cardiac Fibrosis

“…We also demonstrated that mice lacking MKP-5 are resistant to pulmonary fibrosis in response to bleomycin-induced lung injury (27). Mechanistically, these studies indicated that MKP-5 may positively regulate TGF-b1 signaling, which is an underlying mechanism for pathological fibrogenesis (23,27). However, the role of MKP-5 in pathological myocardial fibrosis has yet to be determined.…”

“…Specifically, we have demonstrated that MKP-5 deficiency exerts a protective effect on the progression of muscular dystrophy, including the development of fibrosis in skeletal muscles (23). We also demonstrated that mice lacking MKP-5 are resistant to pulmonary fibrosis in response to bleomycin-induced lung injury (27). Mechanistically, these studies indicated that MKP-5 may positively regulate TGF-b1 signaling, which is an underlying mechanism for pathological fibrogenesis (23,27).…”

“…Evidence has shown that MKP-5 is pivotal in regulating inflammation, immunity, oxidative stress, cancer, insulin resistance, nonalcoholic steatohepatitis, and regenerative myogenesis (19)(20)(21)(22)(23)(24)(25)(26). Our previous studies have revealed the involvement of MKP-5 in the pathogenesis of tissue fibrosis (23,27). Specifically, we have demonstrated that MKP-5 deficiency exerts a protective effect on the progression of muscular dystrophy, including the development of fibrosis in skeletal muscles (23).…”

Pathophysiological Roles of Stress-Activated Protein Kinases in Pulmonary Fibrosis

“…In contrast, mice with a systemic deletion of Dusp10 , which is an equipotent phosphatase of JNK and p38 (also known as MKP-5), show clear resistance to BLM-induced lung fibrosis [ 109 ]. In this situation, macrophages were markedly polarized to the M1 phenotype.…”

Pulmonary fibrosis: something old, something new…still waiting for a breakthrough

“…There has been renewed interest in molecules such as members of the cellular communication network (CCN) ( 12 ) and the insulin-like growth factor (IGF) ( 3 , 22 ) family of proteins and their functions in the setting of lung fibrosis. Moonlighting functions for enzymes such as sialidases ( 11 ) and phosphatases ( 1 , 18 , 21 ) have been identified. Research into mechanisms mediating oxidative stress and its role in lung fibrosis has continued ( 6 ).…”