title: SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells.
abstract: Inflammation plays a crucial role in atherosclerosis. Monocytes/macrophages are some of the cells involved in the inflammatory process in atherogenesis. Autophagy exerts a protective effect against cellular stresses like inflammation, and it is regulated by nutrient-sensing pathways. The nutrient-sensing pathway includes SIRT1, a NAD(+)-dependent histone deacetylase, which is implicated in the regulation of a variety of cellular processes including inflammation and autophagy. The mechanism through which the dysfunction of SIRT1 contributes to the regulation of inflammation in relation to autophagy in monocytes/macrophages is unclear. In the present study, we demonstrate that treatment with 2-[(2-Hydroxynaphthalen-1-ylmethylene)amino]-N-(1-phenethyl)benzamide (Sirtinol), a chemical inhibitor of SIRT1, induces the overexpression of inflammation-related genes such as tumor necrosis factor (TNF)-α and interleukin (IL)-6 through nuclear factor (NF)-κB signaling activation, which is associated with autophagy dysfunction, as shown through p62/Sqstm1 accumulation and decreased expression of light chain (LC) 3 II in THP-1 cells. The autophagy inhibitor, 3-methyladenine, also induces inflammation-related NF-κB activation. In p62/Sqstm1 knockdown cells, Sirtinol-induced inflammation through NF-κB activation is blocked. In addition, inhibition of SIRT1 is involved in the activation of the mammalian target of rapamycin (mTOR) pathway and is implicated in decreased 5'-AMP activated kinase (AMPK) activation, leading to the impairment of autophagy. The mTOR inhibitor, rapamycin, abolishes Sirtinol-induced inflammation and NF-κB activation associated with p62/Sqstm1 accumulation. In summary, SIRT1 inactivation induces inflammation through NF-κB activation and dysregulates autophagy via nutrient-sensing pathways such as the mTOR and AMPK pathways, in THP-1 cells.
authors.affiliation: Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Takeda-Watanabe
authors.forename: Munehiro
authors.initials: M
authors.lastname: Kitada
authors.forename: Keizo
authors.initials: K
authors.lastname: Kanasaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009284:Naphthols / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D009284:Naphthols; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C439060:sirtinol; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1