title: Rebamipide Suppresses Monosodium Urate Crystal-Induced Interleukin-1β Production Through Regulation of Oxidative Stress and Caspase-1 in THP-1 Cells.
abstract: This study investigated the effect of rebamipide on activation of the NLRP3 inflammasome and generation of reactive oxygen species (ROS) in monosodium urate (MSU) crystal-induced interleukin-1β (IL-1β) production. Human monocyte cell line THP-1 and human umbilical venous endothelial cells (HUVECs) were used to assess the inflammatory response to MSU crystals. NADP/NADPH activity assays were used as a marker of ROS generation. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting were performed to evaluate levels of IL-1β, caspase-1, NLRP3, associated speck-like protein (ASC), nuclear factor-κB (NF-κB), p65, IκBα, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1). Experimental pharmaceuticals included rebamipide, colchicine, dexamethasone, and ascorbic acid. In THP-1 cells, treatment with MSU crystals increased NADP/NADPH ratios and IL-1β expression, and both of these responses were potently inhibited by addition of rebamipide. Rebamipide also attenuated enhanced expression of caspase-1 gene by MSU crystals (p < 0.05). Western blotting demonstrated that MSU crystals stimulated caspase-1 but not NLRP3 and ASC activation. Similarly, MSU crystals activated the NF-κB pathway, which in turn was blocked by rebamipide. Stimulation of HUVECs with MSU crystals increased expression of VCAM-1 and ICAM-1, which were markedly inhibited by both rebamipide and dexamethasone. This study demonstrated that rebamipide inhibits IL-1β activation through suppression of ROS-mediated NF-κB signaling pathways and caspase-1 activation in MSU crystal-induced inflammation.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Daegu, Daegu, Republic of Korea. kimsk714@cu.ac.kr.|Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu, Republic of Korea. kimsk714@cu.ac.kr.
authors.forename: Seong-Kyu
authors.initials: SK
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Daegu, Daegu, Republic of Korea.|Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu, Republic of Korea.
authors.forename: Jung-Yoon
authors.initials: JY
authors.lastname: Choe
authors.affiliation: Arthritis and Autoimmunity Research Center, Catholic University of Daegu, Daegu, Republic of Korea.
authors.forename: Ki-Yeun
authors.initials: KY
authors.lastname: Park
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D020170:Caspase 1 / Q000096:biosynthesis*; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006073:Gout / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D053583:Interleukin-1beta / Q000096:biosynthesis*; D009243:NAD / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D015363:Quinolones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014527:Uric Acid / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: C508585:IL1B protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D015363:Quinolones; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D009243:NAD; D018799:Intercellular Adhesion Molecule-1; D014527:Uric Acid; D003907:Dexamethasone; D020170:Caspase 1; C052785:rebamipide; D000409:Alanine; D001205:Ascorbic Acid; D003078:Colchicine
keywords: inflammasome; inflammation; interleukin-1β; rebamipide; uric acid