Induction of HO-1 by Mevastatin Mediated via a Nox/ROS-Dependent c-Src/PDGFRalpha/PI3K/ Akt/ Nrf2/ARE Cascade Suppresses TNF-alpha-Induced Lung Inflammation.

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Title:	Induction of HO-1 by Mevastatin Mediated via a Nox/ROS-Dependent c-Src/PDGFRalpha/PI3K/ Akt/ Nrf2/ARE Cascade Suppresses TNF-alpha-Induced Lung Inflammation.
Authors:	林志中;Lin, Chih-Chung;林維寧;Lin, Wei-Ning;卓若羚;Cho, Rou-Ling;楊建中;Yang, Chien-Chung;葉怡誠;Yeh, Yi-Cheng;蕭立德;Hsiao, Li-Der;曾惠卿;Tseng, Hui-Ching;楊春茂;Yang, Chuen-Mao
Contributors:	學士後獸醫學系
Keywords:	AREs;Nrf2;ROS;heme oxygenase-1;mevastatin.
Date:	2020-01
Issue Date:	2020-11-26 07:03:59 (UTC+0)
Publisher:	亞洲大學
Abstract:	Background: Mevastatin (MVS), a 3-hydroxy-3-methylglutaryl coenzyme, a reductase (HMG-CoA) inhibitor, has anti-inflammatory effects potentially via up-regulation of heme oxygenase-1 (HO-1). However, the mechanisms underlying MVS-induced HO-1 expression remain largely unknown in human pulmonary alveolar epithelial cells (HPAEpiCs). Methods: HO-1 and intercellular adhesion molecule (ICAM)-1 expression were determined using real-time PCR, Western blotting, and promoter reporter analyses. The signaling components were investigated using pharmacological inhibitors or specific small interfering RNA (siRNA)s. Interaction between Nrf2 and the antioxidant response element (ARE) binding site for the HO-1 promoter was determined by chromatin immunoprecipitation (ChIP) assay. Results: Upregulation of HO-1 by MVS attenuated the tumor necrosis factor (TNF)-α-stimulated ICAM-1 expression associated with THP-1 adhesion to HPAEpiCs. These inhibitory effects of HO-1 were reversed by tin protoporphyrin (SnPP)IX or by transfection with HO-1 siRNA. MVS-induced HO-1 expression was mediated via NADPH oxidase (Nox)-derived reactive oxygen species (ROS) generation. Activation of Nox2/ROS further stimulated the phosphorylation of p47phox, proto-oncogene tyrosine-protein kinase (c-Src), platelet-derived growth factor receptor (PDFGR)α, protein kinase B (Akt), and Nrf2, which were inhibited by siRNAs. Pretreatment with pharmacological inhibitors, including diphenyleneiodonium (DPI), apocynin (APO), N-acetyl-L-cysteine (NAC), PP1, AG1296, or LY294002, reduced the MVS-activated Nrf2 nuclear-translocation binding to the ARE on the HO-1 promoter. Conclusions: MVS-induced HO-1 is, at least in part, mediated through a p47phox/Nox2/ROS-dependent activation of c-Src/PDGFRα/PI3K/Akt-regulated Nrf2/ARE axis and suppresses the TNF-α-mediated inflammatory responses in HPAEpiCs.
Relation:	Journal of Clinical Medicine
Appears in Collections:	[Department of Post-Baccalaureate Veterinary Medicine] journal paper

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