TNF-α expression in neutrophils and its regulation by glycogen synthase kinase-3: a potentiating role for lithium.

Autor: Giambelluca MS; Centre de Recherche du Centre Hospitalier Universitaire de Québec and Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; and., Bertheau-Mailhot G; Centre de Recherche du Centre Hospitalier Universitaire de Québec and Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; and., Laflamme C; Centre de Recherche du Centre Hospitalier Universitaire de Québec and Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; and., Rollet-Labelle E; Centre de Recherche du Centre Hospitalier Universitaire de Québec and Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; and., Servant MJ; Faculty of Pharmacy, Université de Montréal, Montréal, Quebec, Canada., Pouliot M; 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.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2014 Aug; Vol. 28 (8), pp. 3679-90. Date of Electronic Publication: 2014 May 06.
DOI: 10.1096/fj.14-251900
Abstrakt: 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.
(© FASEB.)
Databáze: MEDLINE
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