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TNF‐α expression in neutrophils and its regulation by glycogen synthase kinase‐3: A potentiating role for lithium
Author(s) -
Giambelluca Miriam S.,
BertheauMailhot Geneviève,
Laflamme Cynthia,
RolletLabelle Emmanuelle,
Servant Marc J.,
Pouliot Marc
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-251900
Subject(s) - gsk 3 , glycogen synthase , lithium (medication) , gsk3b , chemistry , tumor necrosis factor alpha , kinase , inflammation , microbiology and biotechnology , phosphorylation , pharmacology , endocrinology , medicine , biology , biochemistry
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 (ED 50 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.—Giambelluca, M. S., Bertheau‐Mailhot, G., Laflamme, C., Rollet‐Labelle, E., Servant, M. J., Pouliot, M. TNF‐α expression in neutrophils and its regulation by glycogen synthase kinase‐3: a potentiating role for lithium. FASEB J. 28, 3679–3690 (2014). www.fasebj.org