title: GSK621 activates AMPK signaling to inhibit LPS-induced TNFα production.
abstract: LPS stimulation in macrophages/monocytes induces TNFα production. We here tested the potential effect of GSK621, a novel AMP-activated protein kinase (AMPK) activator, against the process. In RAW264.7 macrophages, murine bone marrow-derived macrophages (BMDMs), and chronic obstructive pulmonary disease (COPD) patients' monocytes, GSK621 significantly inhibited LPS-induced TNFα protein secretion and mRNA synthesis. Inhibition of AMPK, through AMPKα shRNA knockdown or dominant negative mutation (T172A), almost abolished GSK621's suppression on TNFα in RAW264.7 cells. Reversely, forced-expression of a constitutively-active AMPKα (T172D) mimicked GSK621 actions and reduced LPS-induced TNFα production. Molecularly, GSK621 suppressed LPS-induced reactive oxygen species (ROS) production and nuclear factor kappa B (NFκB) activation. In vivo, GSK621 oral administration inhibited LPS-induced TNFα production and endotoxin shock in mice. In summary, GSK621 activates AMPK signaling to inhibit LPS-induced TNFα production in macrophages/monocytes.
authors.affiliation: Department of Medical Technology, Xi'an Medical University, China.
authors.forename: Yong-Hong
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Center of Stomatology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Emergency, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China. Electronic address: drlipingxamu@163.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Medical Technology, Xi'an Medical University, China. Electronic address: liubeixamu@163.com.
authors.forename: Bei
authors.initials: B
authors.lastname: Liu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D007093:Imidazoles / Q000008:administration & dosage*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D051379:Mice; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology*; D011744:Pyrimidinones / Q000008:administration & dosage*; D000067996:RAW 264.7 Cells; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: C000606536:GSK621; D007093:Imidazoles; D008070:Lipopolysaccharides; D011744:Pyrimidinones; D014409:Tumor Necrosis Factor-alpha; D055372:AMP-Activated Protein Kinases
keywords: AMPK; GSK621; LPS; ROS and NFκB; TNFα