title: TNF-α expression in neutrophils and its regulation by glycogen synthase kinase-3: a potentiating role for lithium.
abstract: Glycogen synthase kinase 3 (GSK-3) is associated with several cellular systems, including immune response. Lithium, a widely used pharmacological treatment for bipolar disorder, is a GSK-3 inhibitor. GSK-3α is the predominant isoform in human neutrophils. In this study, we examined the effect of GSK-3 inhibition on the production of TNF-α by neutrophils. In the murine air pouch model of inflammation, lithium chloride (LiCl) amplified TNF-α release. In lipopolysaccharide-stimulated human neutrophils, GSK-3 inhibitors mimicked the effect of LiCl, each potentiating TNF-α release after 4 h, in a concentration-dependent fashion, by up to a 3-fold increase (ED50 of 1 mM for lithium). LiCl had no significant effect on cell viability. A positive association was revealed between GSK-3 inhibition and prolonged activation of the p38/MNK1/eIF4E pathway of mRNA translation. Using lysine and arginine labeled with stable heavy isotopes followed by quantitative mass spectrometry, we determined that GSK-3 inhibition markedly increases (by more than 3-fold) de novo TNF-α protein synthesis. Our findings shed light on a novel mechanism of control of TNF-α expression in neutrophils with GSK-3 regulating mRNA translation and raise the possibility that lithium could be having a hitherto unforeseen effect on inflammatory diseases.
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; and.
authors.forename: Miriam S
authors.initials: MS
authors.lastname: Giambelluca
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; and.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Bertheau-Mailhot
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; and.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Laflamme
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; and.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Rollet-Labelle
authors.affiliation: Faculty of Pharmacy, Université de Montréal, Montréal, Quebec, Canada.
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Servant
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec and Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; and marc.pouliot@crchul.ulaval.ca.
authors.forename: Marc
authors.initials: M
authors.lastname: Pouliot
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation; D008070:Lipopolysaccharides / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology*; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D023421:Models, Animal; D016328:NF-kappa B / Q000378:metabolism; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D040521:Subcutaneous Tissue; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D007211:Indoles; D008070:Lipopolysaccharides; D008301:Maleimides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C417521:SB 216763; D014409:Tumor Necrosis Factor-alpha; C440499:lipopolysaccharide, Escherichia coli O111 B4; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; D018021:Lithium Chloride
keywords: granulocytes; inflammation