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  • Title: Sirtuin 6 inhibits myofibroblast differentiation via inactivating transforming growth factor-β1/Smad2 and nuclear factor-κB signaling pathways in human fetal lung fibroblasts.
    Author: Zhang Q, Tu W, Tian K, Han L, Wang Q, Chen P, Zhou X.
    Journal: J Cell Biochem; 2019 Jan; 120(1):93-104. PubMed ID: 30230565.
    Abstract:
    Fibroblast-to-myofibroblast differentiation, which is characterized by increased expression of α-smooth muscle actin, is known to be involved in the pathogenesis of idiopathic pulmonary fibrosis. Sirtuin 6 (SIRT6), a member of the sirtuin family, has been proved to inhibit epithelial-to-mesenchymal transition during idiopathic pulmonary fibrosis. However, the function of SIRT6 in lung myofibroblast differentiation is still obscure. Transforming growth factor-β1 (TGF-β1) is one of the main factors that can powerfully promote myofibroblast differentiation. In the current study, we aimed to explore the role of SIRT6 in the cellular model of fibroblast-to-myofibroblast differentiation induced by TGF-β1 using human fetal lung fibroblasts (HFL1). We demonstrated that the SIRT6 protein level is upregulated by TGF-β1 in HFL1 cells. Overexpression of SIRT6 significantly suppresses TGF-β1-induced myofibroblast differentiation in HFL1 cells. Mechanistically, SIRT6 decreases phosphorylation and nuclear translocation of Smad2 under TGF-β1 stimulation. Nevertheless, mutant SIRT6 (H133Y) without histone deacetylase activity fails to inhibit phosphorylation and nuclear translocation of Smad2. Meanwhile, SIRT6 interacts with the nuclear factor-κB (NF-κB) subunit p65 and represses TGF-β1-induced NF-κB-dependent transcriptional activity, which is also dependent on its deacetylase activity. Overexpression of wild-type SIRT6 but not the H133Y mutant inhibits the expression of NF-κB-dependent genes including interleukin (IL)-1β, IL-6 and matrix metalloproteinase-9 (MMP-9) induced by TGF-β1, all of which have been demonstrated to promote myofibroblast differentiation. Collectively, our study reveals that SIRT6 prevents TGF-β1-induced lung myofibroblast differentiation through inhibiting TGF-β1/Smad2 and NF-κB signaling pathways.
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