title: Inhibition of GSK-3 reduces prostaglandin E2 production by decreasing the expression levels of COX-2 and mPGES-1 in monocyte/macrophage lineage cells.
abstract: Inflammatory stimuli induce prostaglandin E2 (PGE2) synthesis by upregulating cycloxgenase-2 (COX-2) and microsomal PGE synthase-1 (mPGES-1). Glycogen synthase kinase-3 (GSK-3) reportedly plays an important role in inflammatory reactions, whereas the role of this enzyme in inflammatory PGE2 production remains unclear. In the present study, therefore, we examined whether inhibition of GSK-3 can reduce inflammatory PGE2 production in vitro and in vivo. When macrophage-like cells differentiated from THP-1 were stimulated with lipopolysaccharide (LPS), PGE2 production and the expression levels of COX-2 and mPGES-1 were markedly elevated. GSK-3 inhibitors LiCl and SB216763 strongly suppressed their protein levels through inhibition of mRNA expressions. Subsequently, we examined the effect of GSK-3 inhibitors on nuclear factor κB (NF-κB) and early growth response-1 (Egr-1). The GSK-3 inhibitors had no significant effect on the NF-κB pathway, whereas they significantly decreased the expression level of Egr-1. Pharmacological and genetic inhibitions of GSK-3 also strongly suppressed PGE2 production in cultured peritoneal macrophages and in inflammatory air pouches made under the skin of living mice. These results suggested that GSK-3 plays a key role in PGE2 production by increasing COX-2 and mPGES-1 probably through Egr-1-mediated transcription and GSK-3 inhibitors may be potential as novel anti-inflammatory drugs.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Oral-Maxillofacial Surgery, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Noma
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan; Global Medical Science Education Unit, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: yanaga@clipharm.med.kyushu-u.ac.jp.
authors.forename: Fumi
authors.initials: F
authors.lastname: Takahashi-Yanaga
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Arioka
authors.affiliation: Department of Oral-Maxillofacial Surgery, Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sasaguri
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002460:Cell Line; D019070:Cell Lineage; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D051766:Early Growth Response Protein 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D051766:Early Growth Response Protein 1; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; D047428:Protein Kinase Inhibitors; C417521:SB 216763; D051546:Cyclooxygenase 2; D038362:Glycogen Synthase Kinase 3; D000071876:Prostaglandin-E Synthases; D018021:Lithium Chloride; D015232:Dinoprostone
keywords: Anti-inflammatory drug; COX-2; GSK-3; PGE(2); mPGES-1