Accumulative evidence shows a role of the immune system in susceptibility to depression. Proinflammatory cytokines have been shown to be involved in the induction of depressive behavior both in humans and mice, opening a new avenue of therapeutic strategy. Because glycogen synthase kinase-3 (GSK3) was recently identified to be controlling the production of proinflammatory cytokines, and GSK3 has been shown to be implicated in mood disorders for many years, it has been proposed that the proinflammatory action of GSK3 could be responsible for the increased susceptibility to depressive behavior. Moreover, besides regulating cytokines, GSK3 also promotes differentiation of proinflammatory subtypes of Th cells, which are sufficient to induce depressive behavior in mice. Although the clear involvement of the immune system during depressive behavior still needs to be firmly demonstrated, there is growing evidence for the involvement of inflammation in the induction of depressive behavior.

Keywords:
Depression, Glycogen synthase kinase-3, Proinflammatory cytokines, Inflammation
1.
Cohen P, Frame S: The renaissance of GSK3. Nat Rev Mol Cell Biol 2001;2:769-776.
2.
Doble BW, Woodgett JR: GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 2003;116:1175-1186.
3.
Jope RS, Johnson GV: The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 2004;29:95-102.
4.
Jope RS: Glycogen synthase kinase-3 in the etiology and treatment of mood disorders. Front Mol Neurosci 2011;4:16.
5.
Klein PS, Melton DA: A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 1996;93:8455-8459.
6.
Li X, Zhu W, Roh MS, Friedman AB, Rosborough K, Jope RS: In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain. Neuropsychopharmacology 2004;29:1426-1431.
7.
Beurel E, Song L, Jope RS: Inhibition of glycogen synthase kinase-3 is necessary for the rapid antidepressant effect of ketamine in mice. Mol Psychiatry 2011;16:1068-1070.
8.
McManus EJ, Sakamoto K, Armit LJ, Ronaldson L, Shpiro N, Marquez R, Alessi DR: Role that phosphorylation of GSK3 plays in insulin and Wnt signalling defined by knockin analysis. EMBO J 2005;24:1571-1583.
9.
Gould TD, Gray NA, Manji HK: Effects of a glycogen synthase kinase-3 inhibitor, lithium, in adenomatous polyposis coli mutant mice. Pharmacol Res 2003;48:49-53.
10.
Kaidanovich-Beilin O, Milman A, Weizman A, Pick CG, Eldar-Finkelman H: Rapid antidepressive-like activity of specific glycogen synthase kinase-3 inhibitor and its effect on β-catenin in mouse hippocampus. Biol Psychiatry 2004;55:781-784.
11.
Beaulieu JM, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, Gainetdinov RR, Caron MG: Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency. Proc Natl Acad Sci USA 2008;105:1333-1338.
12.
Kaidanovich-Beilin O, Lipina TV, Takao K, van Eede M, Hattori S, Laliberte C, Khan M, Okamoto K, Chambers JW, Fletcher PJ, MacAulay K, Doble BW, Henkelman M, Miyakawa T, Roder J, Woodgett JR: Abnormalities in brain structure and behavior in GSK3α mutant mice. Mol Brain 2009;2:35.
13.
O'Brien WT, Harper AD, Jove F, Woodgett JR, Maretto S, Piccolo S, Klein PS: Glycogen synthase kinase-3β haploinsufficiency mimics the behavioral and molecular effects of lithium. J Neurosci 2004;24:6791-6798.
14.
Omata N, Chiu CT, Moya PR, Leng Y, Wang Z, Hunsberger JG, Leeds P, Chuang DM: Lentivirally mediated GSK-3β silencing in the hippocampal dentate gyrus induces antidepressant-like effects in stressed mice. Int J Neuropsychopharmacol 2011;14:711-717.
15.
Faria MS, Teixeira NA: Reversal of learned helplessness by chronic lithium treatment at a prophylactic level. Braz J Med Biol Res 1993;26:1201-1212.
16.
Nixon MK, Hascoet M, Bourin M, Colombel MC: Additive effects of lithium and antidepressants in the forced swimming test: further evidence for involvement of the serotoninergic system. Psychopharmacology (Berl) 1994;115:59-64.
17.
Mai L, Jope RS, Li X: BDNF-mediated signal transduction is modulated by GSK3β and mood stabilizing agents. J Neurochem 2002;82:75-83.
18.
Warner-Schmidt JL, Duman RS: VEGF as a potential target for therapeutic intervention in depression. Curr Opin Pharmacol 2008;8:14-19.
19.
Polter A, Beurel E, Yang S, Garner R, Song L, Miller CA, Sweatt JD, McMahon L, Bartolucci AA, Li X, Jope RS: Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances. Neuropsychopharmacology 2010;35:1761-1774.
20.
Wilkinson MB, Dias C, Magida J, Mazei-Robison M, Lobo M, Kennedy P, Dietz D, Covington H 3rd, Russo S, Neve R, Ghose S, Tamminga C, Nestler EJ: A novel role of the Wnt-dishevelled-GSK3β signaling cascade in the mouse nucleus accumbens in a social defeat model of depression. J Neurosci 2011;31:9084-9092.
21.
Beaulieu JM, Sotnikova TD, Yao WD, Kockeritz L, Woodgett JR, Gainetdinov RR, Caron MG: Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc Natl Acad Sci USA 2004;101:5099-5104.
22.
Li X, Friedman AB, Zhu W, Wang L, Boswell S, May RS, Davis LL, Jope RS: Lithium regulates glycogen synthase kinase-3β in human peripheral blood mononuclear cells: implication in the treatment of bipolar disorder. Biol Psychiatry 2007;61:216-222.
23.
Karege F, Perroud N, Burkhardt S, Schwald M, Ballmann E, La Harpe R, Malafosse A: Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase kinase-3β in ventral prefrontal cortex of depressed suicide victims. Biol Psychiatry 2007;61:240-245.
24.
Adli M, Hollinde DL, Stamm T, Wiethoff K, Tsahuridu M, Kirchheiner J, Heinz A, Bauer M: Response to lithium augmentation in depression is associated with the glycogen synthase kinase 3-beta -50T/C single nucleotide polymorphism. Biol Psychiatry 2007;62:1295-1302.
25.
Martin M, Rehani K, Jope RS, Michalek SM: Toll-like receptor-mediated cytokine production is differentially regulated by glycogen synthase kinase 3. Nat Immunol 2005;6:777-784.
26.
Beurel E, Michalek SM, Jope RS: Innate and adaptive immune responses regulated by glycogen synthase kinase-3 (GSK3). Trends Immunol 2010;31:24-31.
27.
Wang H, Brown J, Gu Z, Garcia CA, Liang R, Alard P, Beurel E, Jope RS, Greenway T, Martin M: Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-β-signaling pathways regulates the innate inflammatory response. J Immunol 2011;186:5217-5226.
28.
O'Shea JJ, Paul WE: Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010;327:1098-1102.
29.
Graham JA, Fray M, de Haseth S, Lee KM, Lian MM, Chase CM, Madsen JC, Markmann J, Benichou G, Colvin RB, Cosimi AB, Deng S, Kim J, Alessandrini A: Suppressive regulatory T cell activity is potentiated by glycogen synthase kinase 3β inhibition. J Biol Chem 2010;285:32852-32859.
30.
Beurel E, Kaidanovich-Beilin O, Yeh WI, Song L, Palomo V, Michalek SM, Woodgett JR, Harrington LE, Eldar-Finkelman H, Martinez A, Jope RS: Regulation of Th1 cells and experimental autoimmune encephalomyelitis by glycogen synthase kinase-3. J Immunol 2013;190:5000-5011.
31.
Beurel E, Yeh WI, Michalek SM, Harrington LE, Jope RS: Glycogen synthase kinase 3 is an early determinant in the differentiation of pathogenic Th17 cells. J Immunol 2011;186:1391-1398.
32.
Gulen MF, Bulek K, Xiao H, Yu M, Gao J, Sun L, Beurel E, Kaidanovich-Beilin O, Fox PL, DiCorleto PE, Wang JA, Qin J, Wald DN, Woodgett JR, Jope RS, Carman J, Dongre A, Li X: Inactivation of the enzyme GSK3α by the kinase IKKi promotes AKT-mTOR signaling pathway that mediates interleukin-1-induced Th17 cell maintenance. Immunity 2012;37:800-812.
33.
Sengupta S, Jayaraman P, Chilton PM, Casella CR, Mitchell TC: Unrestrained glycogen synthase kinase-3 beta activity leads to activated T cell death and can be inhibited by natural adjuvant. J Immunol 2007;178:6083-6091.
34.
Belmaker RH, Agam G: Major depressive disorder. N Engl J Med 2008;358:55-68.
35.
Greden JF: The burden of recurrent depression: causes, consequences, and future prospects. J Clin Psychiatry 2001;62(suppl 22):5-9.
36.
Miller AH, Maletic V, Raison CL: Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009;65:732-741.
37.
Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, Pollmacher T: Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 2001;58:445-452.
38.
Dantzer R, Kelley KW: Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 2007;21:153-160.
39.
Anisman H, Merali Z: Cytokines, stress and depressive illness: brain-immune interactions. Ann Med 2003;35:2-11.
40.
Miller AH: Depression and immunity: a role for T cells? Brain Behav Immun 2010;24:1-8.
41.
Beurel E, Harrington LE, Jope RS: Inflammatory T helper 17 cells promote depression-like behavior in mice. Biol Psychiatry 2013;73:622-630.
42.
Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E, Miller AH: A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 2013;70:31-41.
© 2014 S. Karger AG, Basel
2014
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.