[No authors listed]
Pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. Secreted protein acidic and rich in cysteine is a matricellular protein that participates in the assembly and turnover of the extracellular matrix, whose expression is regulated by transforming growth factor (TGF)-β1 through activation of mammalian target of rapamycin complex 2 (mTORC2). Exchange factor found in platelets, leukemic, and neuronal tissues (XPLN) is an endogenous inhibitor of mTORC2. However, whether XPLN modulates expression remains unknown. Herein, we investigated the regulatory mechanisms of XPLN in human lung fibroblasts. Effect of XPLN on mTORC2 activity was evaluated by silencing XPLN in human foetal lung fibroblasts (HFL-1 cells), using small interfering RNA. duanyu1842RC expression was quantified by quantitative real-time RT-PCR and western blotting. Fibroblasts were treated with TGF-β1, histone deacetylase (HDAC) inhibitors, entinostat, or vorinostat, to assess their effects on XPLN expression. Moreover, the effect of mTORC1 inhibition on duanyu1842RC and XPLN was examined. XPLN depletion stimulated duanyu1842RC expression and Akt phosphorylation on Ser473. TGF-β1 treatment down-regulated XPLN via Smad 2/3. XPLN mRNA expression was up-regulated upon treatment with HDAC inhibitors in a concentration-dependent manner, and TGF-β1-induced duanyu1842RC expression was reversed by entinostat treatment. mTORC1 inhibition by rapamycin and Raptor depletion stimulated duanyu1842RC expression. In conclusion, this is the first study describing the involvement of XPLN in the regulation of These findings may help uncover the regulatory mechanisms of the axis. The up-regulation of XPLN by HDAC inhibitors may be a novel therapeutic approach in patients with IPF.
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