title: Resolvin D1, resolvin D2 and maresin 1 activate the GSK3β anti-inflammatory axis in TLR4-engaged human monocytes.
abstract: Pro-resolving, docosahexaenoic acid-derived mediators have recently emerged as important potential therapeutic agents for the amelioration of complications arising from inflammation, such as vascular disease, asthma, acute lung injury and colitis. While resolvin D1 (RVD1), resolvin D2 (RVD2) and maresin 1 (MaR1) are established pro-resolvins, their mechanisms of action remain unclear. Here we show that, in LPS-stimulated primary human monocytes, RVD1, RVD2 and MaR1 each suppress the release of pro-inflammatory cytokines (TNF, IL-1β, IL-8) and the innate/adaptive bridging cytokine, IL-12 p40, while simultaneously augmenting the production of the anti-inflammatory cytokine, IL-10. Such resolving activity is accompanied by the increased phosphorylation (enhanced anti-inflammatory state) of glycogen synthase kinase 3β (GSK3β) along with increased phosphorylation (activation) of Akt, SGK1 and CREB but not MAPK-related molecules. Gain and loss of function experiments confirm a key role for GSK3β and CREB in the anti-inflammatory actions of resolvins. These results suggest that induction of the GSK3β anti-inflammatory axis is a common mechanism of action for RVD1, RVD2 and MaR1.
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville, Louisville, KY, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville, Louisville, KY, USA.
authors.forename: Gwyneth J
authors.initials: GJ
authors.lastname: Lamont
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville, Louisville, KY, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lamont
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville, Louisville, KY, USA Department of Medicine, University of Louisville, KY, USA.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Uriarte
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville, Louisville, KY, USA.
authors.forename: Huizhi
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Oral Immunology and Infectious Diseases, University of Louisville, Louisville, KY, USA david.scott@louisville.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008301:Maleimides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000893:Anti-Inflammatory Agents; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D004281:Docosahexaenoic Acids; D000071679:Glycogen Synthase Kinase 3 beta; D017874:Immediate-Early Proteins; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; D000099184:Serum-Glucocorticoid Regulated Kinases; C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; C115163:CREB1 protein, human; C417521:SB 216763; C495345:TLR4 protein, human; C518399:resolvin D1; C545423:resolvin D2
keywords: CREB; GSK3β; LPS; inflammation; maresin; resolvin