title: Bisgma stimulates prostaglandin E2 production in macrophages via cyclooxygenase-2, cytosolic phospholipase A2, and mitogen-activated protein kinases family.
abstract: BACKGROUND
  Bisphenol A-glycidyl-methacrylate (BisGMA) employs as a monomer in dental resins. The leakage of BisGMA from composite resins into the peripheral environment can result in inflammation via macrophage activation. Prostaglandin E2 (PGE2) is a key regulator of immunopathology in inflammatory reactions. Little is known about the mechanisms of BisGMA-induced PGE2 expression in macrophage. The aim of this study was to evaluate the signal transduction pathways of BisGMA-induced PGE2 production in murine RAW264.7 macrophages.
  
  
  RESULTS
  Herein, we demonstrate that BisGMA can exhibit cytotoxicity to RAW264.7 macrophages in a dose- and time-dependent manner (p<0.05). In addition, PGE2 production, COX-2 expression, and cPLA2 phosphorylation were induced by BisGMA on RAW264.7 macrophages in a dose- and time-dependent manner (p<0.05). Moreover, BisGMA could induce the phosphorylation of ERK1/2 pathway (MEK1/2, ERK1/2, and Elk), p38 pathway (MEK3/6, p38, and MAPKAPK2), and JNK pathway (MEK4, JNK, and c-Jun) in a dose- and time-dependent manner (p<0.05). Pretreatment with AACOCF3, U0126, SB203580, and SP600125 significantly diminished the phosphorylation of cPLA2, ERK1/2, p38, and JNK stimulated by BisGMA, respectively (p<0.05). BisGMA-induced cytotoxicity, cPLA2 phosphorylation, PGE2 generation, and caspases activation were reduced by AACOCF3, U0126, SB203580, and SP600125, respectively (p<0.05).
  
  
  CONCLUSIONS
  These results suggest that BisGMA induced-PGE2 production may be via COX-2 expression, cPLA2 phosphorylation, and the phosphorylation of MAPK family. Cytotoxicity mediated by BisGMA may be due to caspases activation through the phosphorylation of cPLA2 and MAPKs family.
authors.affiliation: Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Kuan
authors.affiliation: Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Fu-Mei
authors.initials: FM
authors.lastname: Huang
authors.affiliation: School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shiuan-Shinn
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Li
authors.affiliation: Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan ; School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yu-Chao
authors.initials: YC
authors.lastname: Chang
mesh_terms: D000180:Acrylic Resins / Q000494:pharmacology*; D000818:Animals; D017438:Bisphenol A-Glycidyl Methacrylate / Q000494:pharmacology*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015232:Dinoprostone / Q000819:agonists / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054510:Phospholipases A2, Cytosolic / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000180:Acrylic Resins; D047428:Protein Kinase Inhibitors; D017438:Bisphenol A-Glycidyl Methacrylate; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020928:Mitogen-Activated Protein Kinases; D054510:Phospholipases A2, Cytosolic; D020169:Caspases; D015232:Dinoprostone