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: Miriam S Giambelluca, Geneviève Bertheau-Mailhot, Cynthia Laflamme, Emmanuelle Rollet-Labelle, Marc J Servant, Marc Pouliot
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 28 Issue 8 Pg. 3679-90 (Aug 2014) ISSN: 1530-6860 [Electronic] United States
• PMID: 24803542 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• CREB1 protein, human
• Cyclic AMP Response Element-Binding Protein
• Cytokines
• Indoles
• Lipopolysaccharides
• Maleimides
• NF-kappa B
• Protein Kinase Inhibitors
• RNA, Messenger
• SB 216763
• Tumor Necrosis Factor-alpha
• lipopolysaccharide, Escherichia coli O111 B4
• Glycogen Synthase Kinase 3
• glycogen synthase kinase 3 alpha
• Lithium Chloride

Topics

• Animals
• Cells, Cultured
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Cytokines (biosynthesis, genetics)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, physiology)
• Humans
• Indoles (pharmacology)
• Inflammation
• Lipopolysaccharides (pharmacology)
• Lithium Chloride (pharmacology)
• Maleimides (pharmacology)
• Mice
• Models, Animal
• NF-kappa B (metabolism)
• Neutrophil Infiltration
• Neutrophils (enzymology, metabolism)
• Protein Biosynthesis (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• RNA, Messenger (biosynthesis, genetics)
• Signal Transduction (drug effects, physiology)
• Subcutaneous Tissue
• Tumor Necrosis Factor-alpha (biosynthesis, genetics, metabolism)