Journal Mobile Options
Table of Contents
Vol. 56, No. 2-3, 2007
Issue release date: February 2008

Monocytic, Th1 and Th2 Cytokine Alterations in the Pathophysiology of Schizophrenia

Na K.-S. · Kim Y.-K.
To view the fulltext, log in and/or choose pay-per-view option

Individual Users: Register with Karger Login Information

Please create your User ID & Password





Contact Information











I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in

Abstract

A growing body of evidence suggests that changes in the serum levels and cellular production of various cytokines are associated with the immunological abnormalities of schizophrenia. Several studies have examined alterations in T helper type 1 (Th1) and T helper type 2 (Th2) cytokines in schizophrenia. We explored monocytic, Th1 and Th2 cytokines in 43 schizophrenia patients and 50 normal controls. The mitogen-induced production of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-4, γ-interferon (IFN-γ) and IL-2 was measured with enzyme-linked immunosorbent assays before and after antipsychotic treatment. IL-6 and TNF-α production by schizophrenic patients was significantly higher than by normal controls, while IL-2, IL-4 and IFN-γ production was significantly lower in schizophrenic patients. After 6 weeks of antipsychotic treatment, IL-6 and TNF-α production was significantly decreased, while IL-4, IFN-γ and IL-2 productions were not significantly changed. Our results suggest that increased monocytic cytokines and decreased Th1 and Th2 cytokines may be associated with the immunopathogenesis of acute psychotic schizophrenia, and that antipsychotics may play an important role in immune response by decreasing elevated monocytic cytokines.



Copyright / Drug Dosage

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 or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
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 goverment 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.

References

  1. Kirch DG: Infection and autoimmunity as etiologic factors in schizophrenia: a review and reappraisal. Schizophr Bull 1993;19:355–370.
  2. Jones AL, Mowry BJ, Pender MP, Greer JM: Immune dysregulation and self-reactivity in schizophrenia: do some cases of schizophrenia have an autoimmune basis? Immunol Cell Biol 2005;83:9–17.
  3. Kim YK: The role of cytokine network in pathophysiology of schizophrenia. Curr Psychiatry Rev 2005;1:123–131.
  4. Muller N, Riedel M, Ackenheil M, Schwarz MJ: The role of immune function in schizophrenia: an overview. Eur Arch Psychiatry Clin Neurosci 1999;249(suppl 4):62–68.

    External Resources

  5. Yao JK, van Kammen DP: Membrane phospholipids and cytokine interaction in schizophrenia. Int Rev Neurobiol 2004;59:297–326.
  6. Kim YK, Kim L, Lee MS: Relationships between interleukins, neurotransmitters and psychopathology in drug-free male schizophrenics. Schizophr Res 2000;44:165–175.
  7. Ozaki K, Leonard WJ: Cytokine and cytokine receptor pleiotropy and redundancy. J Biol Chem 2002;277:29355–29358.
  8. McGeer PL, McGeer EG: The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995;21:195–218.
  9. Breder CD, Tsujimoto M, Terano Y, Scott DW, Saper CB: Distribution and characterization of tumor necrosis factor-alpha-like immunoreactivity in the murine central nervous system. J Comp Neurol 1993;337:543–567.
  10. Watkins LR, Maier SF, Goehler LE: Cytokine-to-brain communication: a review and analysis of alternative mechanisms. Life Sci 1995;57:1011–1026.
  11. Kronfol Z, Remick DG: Cytokines and the brain: implications for clinical psychiatry. Am J Psychiatry 2000;157:683–694.
  12. Banks WA: Blood-brain barrier transport of cytokines: a mechanism for neuropathology. Curr Pharm Des 2005;11:973–984.
  13. Rothwell NJ, Relton JK: Involvement of cytokines in acute neurodegeneration in the CNS. Neurosci Biobehav Rev 1993;17:217–227.
  14. Sredni-Kenigsbuch D: Th1/Th2 cytokines in the central nervous system. Int J Neurosci 2002;112:665–703.
  15. Rothermundt M, Arolt V, Weitzsch C, Eckhoff D, Kirchner H: Production of cytokines in acute schizophrenic psychosis. Biol Psychiatry 1996;40:1294–1297.
  16. Wilke I, Arolt V, Rothermundt M, Weitzsch C, Hornberg M, Kirchner H: Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 1996;246:279–284.
  17. Kim YK, Lee MS, Suh KY: Decreased interleukin-2 production in Korean schizophrenic patients. Biol Psychiatry 1998;43:701–704.
  18. Kim YK, Suh IB, Kim H, Han CS, Lim CS, Choi SH, Licinio J: The plasma levels of interleukin-12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Mol Psychiatry 2002;7:1107– 1114.
  19. Cazzullo CL, Scarone S, Grassi B, Vismara C, Trabattoni D, Clerici M, Clerici M: Cytokines production in chronic schizophrenia patients with or without paranoid behaviour. Prog Neuropsychopharmacol Biol Psychiatry 1998;22:947–957.
  20. Cazzullo CL, Sacchetti E, Galluzzo A, Panariello A, Colombo F, Zagliani A, Clerici M: Cytokine profiles in drug-naive schizophrenic patients. Schizophr Res 2001;47:293–298.
  21. Rothermundt M, Arolt V, Weitzsch C, Eckhoff D, Kirchner H: Immunological dysfunction in schizophrenia: a systematic approach. Neuropsychobiology 1998;37:186– 193.
  22. Barak V, Barak Y, Levine J, Nisman B, Roisman I: Changes in interleukin-1 beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic patients. J Basic Clin Physiol Pharmacol 1995;6:61–69.
  23. Baker I, Masserano J, Wyatt RJ: Serum cytokine concentrations in patients with schizophrenia. Schizophr Res 1996;20:199–203.
  24. Theodoropoulou S, Spanakos G, Baxevanis CN, Economou M, Gritzapis AD, Papamichail MP, Stefanis CN: Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res 2001;47:13–25.
  25. Erbagci AB, Herken H, Koyluoglu O, Yilmaz N, Tarakcioglu M: Serum IL-1beta, sIL-2r, IL-6, IL-8 and TNF-alpha in schizophrenic patients, relation with symptomatology and responsiveness to risperidone treatment. Mediators Inflamm 2001;10:109–115.
  26. Sirota P, Schild K, Elizur A, Djaldetti M, Fishman P: Increased interleukin-1 and interleukin-3 like activity in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 1995;19:75–83.
  27. Bessler H, Levental Z, Karp L, Modai I, Djaldetti M, Weizman A: Cytokine production in drug-free and neuroleptic-treated schizophrenic patients. Biol Psychiatry 1995;38:297–302.
  28. Schattner A, Cori Y, Hahn T, Sirota P: No evidence for autoimmunity in schizophrenia. J Autoimmun 1996;9:661–666.
  29. Frommberger UH, Bauer J, Haselbauer P, Fraulin A, Riemann D, Berger M: Interleukin-6-(IL-6) plasma levels in depression and schizophrenia: comparison between the acute state and after remission. Eur Arch Psychiatry Clin Neurosci 1997;247:228–233.
  30. Zhang XY, Zhou DF, Zhang PY, Wu GY, Cao LY, Shen YC: Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology. Schizophr Res 2002;57:247–258.
  31. Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kuhn M, Schuld A, Pollmacher T: Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res 1999;33:407–418.
  32. Katila H, Appelberg B, Hurme M, Rimon R: Plasma levels of interleukin-1 beta and interleukin-6 in schizophrenia, other psychoses, and affective disorders. Schizophr Res 1994;12:29–34.
  33. Jansen MJ, Hendriks T, Knapen MF, van Kempen LC, van der Meer JW, Goris RJ: Chlorpromazine down-regulates tumor necrosis factor-alpha and attenuates experimental multiple organ dysfunction syndrome in mice. Crit Care Med 1998;26:1244–1250.
  34. Kiku Y, Matsuzawa H, Ohtsuka H, Terasaki N, Fukuda S, Kon-Nai S, Koiwa M, Yokomizo Y, Sato H, Rosol TJ, Okada H, Yoshino TO: Effects of chlorpromazine, pentoxifylline and dexamethasone on mRNA expression of lipopolysaccharide-induced inflammatory cytokines in bovine peripheral blood mononuclear cells. J Vet Med Sci 2002;64:723–726.
  35. Lu LX, Guo SQ, Chen W, Li Q, Cheng J, Guo JH: Effect of clozapine and risperidone on serum cytokine levels in patients with first–episode paranoid schizophrenia. Di Yi Jun Yi Da Xue Xue Bao 2004;24:1251–1254.

    External Resources

  36. Maes M, Bosmans E, Kenis G, De Jong R, Smith RS, Meltzer HY: In vivo immunomodulatory effects of clozapine in schizophrenia. Schizophr Res 1997;26:221–225.
  37. Pollmacher T, Hinze-Selch D, Mullington J: Effects of clozapine on plasma cytokine and soluble cytokine receptor levels. J Clin Psychopharmacol 1996;16:403–409.
  38. Monteleone P, Fabrazzo M, Tortorella A, Maj M: Plasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: effects of clozapine treatment. Psychiatry Res 1997;71:11–17.
  39. Kim DJ, Kim W, Yoon SJ, Go HJ, Choi BM, Jun TY, Kim YK: Effect of risperidone on serum cytokines. Int J Neurosci 2001;111:11–19.
  40. Cazzullo CL, Sacchetti E, Galluzzo A, Panariello A, Adorni A, Pegoraro M, Bosis S, Colombo F, Trabattoni D, Zagliani A, Clerici M: Cytokine profiles in schizophrenic patients treated with risperidone: a 3-month follow-up study. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:33–39.
  41. Zhang XY, Zhou DF, Cao LY, Zhang PY, Wu GY, Shen YC: Changes in serum interleukin-2, -6, and -8 levels before and during treatment with risperidone and haloperidol: relationship to outcome in schizophrenia. J Clin Psychiatry 2004;65:940–947.
  42. Leykin I, Mayer R, Shinitzky M: Short and long-term immunosuppressive effects of clozapine and haloperidol. Immunopharmacology 1997;37:75–86.
  43. Rudolf S, Peters M, Rothermundt M, Arolt V, Kirchner H: The influence of typical and atypical neuroleptic drugs in the production of interleukin-2 and interferon-gamma in vitro. Neuropsychobiology 2002;46:180–185.
  44. APA: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, American Psychiatric Press, 1994.
  45. First M, Spitzer RL, Gibbon M, William JB: Structured Clinical Interview for DSM-IV Axis I Disorder – Patient Edition (scid-i/p, version 2.0). New York, Biometrics Research Department, New York State Psychiatric Institute, 1998.
  46. Kay SR, Fiszbein A, Opler LA: The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13:261–276.
  47. De Groote D, Zangerle PF, Gevaert Y, Fassotte MF, Beguin Y, Noizat-Pirenne F, Pirenne J, Gathy R, Lopez M, Dehart I, et al: Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation. Cytokine 1992;4:239–248.
  48. Muller N, Riedel M, Ackenheil M, Schwarz MJ: Cellular and humoral immune system in schizophrenia: a conceptual re-evaluation. World J Biol Psychiatry 2000;1:173–179.
  49. Schwarz MJ, Chiang S, Muller N, Ackenheil M: T-helper-1 and T-helper-2 responses in psychiatric disorders. Brain Behav Immun 2001;15:340–370.
  50. Pae CU, Yoon CH, Kim TS, Kim JJ, Park SH, Lee CU, Lee SJ, Lee C, Paik IH: Antipsychotic treatment may alter T-helper (Th) 2 arm cytokines. Int Immunopharmacol 2006;6:666–671.
  51. Kim YK, Myint AM, Lee BH, Han CS, Lee HJ, Kim DJ, Leonard BE: Th1, Th2 and Th3 cytokine alteration in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2004;28:1129–1134.
  52. Schibler KR, Liechty KW, White WL, Rothstein G, Christensen RD: Defective production of interleukin-6 by monocytes: a possible mechanism underlying several host defense deficiencies of neonates. Pediatr Res 1992;31:18–21.
  53. Gadient RA, Otten U: Expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6r) mRNAs in rat brain during postnatal development. Brain Res 1994;637:10–14.
  54. Mizuno T, Sawada M, Suzumura A, Marunouchi T: Expression of cytokines during glial differentiation. Brain Res 1994;656:141–146.
  55. Gadient RA, Otten UH: Interleukin-6 (IL-6) – a molecule with both beneficial and destructive potentials. Prog Neurobiol 1997;52:379–390.
  56. Arolt V, Rothermundt M, Wandinger KP, Kirchner H: Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment. Mol Psychiatry 2000;5:150–158.
  57. Nikkila HV, Muller K, Ahokas A, Rimon R, Andersson LC: Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res 2001;49:99–105.
  58. Moots RJ, Al-Saffar Z, Hutchinson D, Golding SP, Young SP, Bacon PA, McLaughlin PJ: Old drug, new tricks: haloperidol inhibits secretion of proinflammatory cytokines. Ann Rheum Dis 1999;58:585–587.
  59. Nikkila HV, Muller K, Ahokas A, Miettinen K, Rimon R, Andersson LC: Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes. Am J Psychiatry 1999;156:1725–1729.
  60. Zou JY, Crews FT: TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: neuroprotection by NF kappa B inhibition. Brain Res 2005;1034:11–24.
  61. Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL, Marinovich M: Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the SRC family of kinases. J Neurosci 2003;23:8692–8700.
  62. Paterson GJ, Ohashi Y, Reynolds GP, Pratt J, Morris BJ: Selective increases in the cytokine, TNFalpha, in the prefrontal cortex of PCP-treated rats and human schizophrenic subjects: influence of antipsychotic drugs. J Psychopharmacol 2006; 20:636–642.
  63. Ganguli R, Brar JS, Chengappa KR, DeLeo M, Yang ZW, Shurin G, Rabin BS: Mitogen-stimulated interleukin-2 production in never-medicated, first-episode schizophrenic patients: the influence of age at onset and negative symptoms. Arch Gen Psychiatry 1995;52:668–672.
  64. Hornberg M, Arolt V, Wilke I, Kruse A, Kirchner H: Production of interferons and lymphokines in leukocyte cultures of patients with schizophrenia. Schizophr Res 1995;15:237–242.
  65. Gomez CR, Boehmer ED, Kovacs EJ: The aging innate immune system. Curr Opin Immunol 2005;17:457–462.
  66. Butcher S, Chahel H, Lord JM: Ageing and the neutrophil: no appetite for killing? Immunology 2000;100:411–416.
  67. Bauer J, Strauss S, Schreiter-Gasser U, Ganter U, Schlegel P, Witt I, Yolk B, Berger M: Interleukin-6 and alpha-2-macroglobulin indicate an acute-phase state in Alzheimer’s disease cortices. FEBS Lett 1991;285:111–114.
  68. Licastro F, Pedrini S, Caputo L, Annoni G, Davis LJ, Ferri C, Casadei V, Grimaldi LM: Increased plasma levels of interleukin-1, interleukin-6 and alpha-1-antichymotrypsin in patients with Alzheimer’s disease: peripheral inflammation or signals from the brain? J Neuroimmunol 2000;103:97–102.
  69. Johnson JD, O’Connor KA, Deak T, Stark M, Watkins LR, Maier SF: Prior stressor exposure sensitizes LPS-induced cytokine production. Brain Behav Immun 2002;16:461–476.
  70. Kim YK, Maes M: The role of cytokine network in psychological stress. Acta Neuropsychiatr 2003;15:148–155.

    External Resources

  71. DeRijk R, Michelson D, Karp B, Petrides J, Galliven E, Deuster P, Paciotti G, Gold PW, Sternberg EM: Exercise and circadian rhythm-induced variations in plasma cortisol differentially regulate interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF alpha) production in humans: high sensitivity of TNF alpha and resistance of IL-6. J Clin Endocrinol Metab 1997;82:2182–2191.
  72. Guidi L, Tricerri A, Vangeli M, Frasca D, Riccardo Errani A, Di Giovanni A, Antico L, Menini E, Sciamanna V, Magnavita N, Doria G, Bartoloni C: Neuropeptide Y plasma levels and immunological changes during academic stress. Neuropsychobiology 1999;40:188–195.
  73. Phaybouth V, Wang SZ, Hutt JA, McDonald JD, Harrod KS, Barrett EG: Cigarette smoke suppresses Th1 cytokine production and increases RSV expression in a neonatal model. Am J Physiol Lung Cell Mol Physiol 2006;290:L222–L231.
  74. Yang SR, Chida AS, Bauter MR, Shafiq N, Seweryniak K, Maggirwar SB, Kilty I, Rahman I: Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol 2006;291:L46–L57.
  75. Ouyang Y, Virasch N, Hao P, Aubrey MT, Mukerjee N, Bierer BE, Freed BM: Suppression of human IL-1beta, IL-2, IFN-gamma, and TNF-alpha production by cigarette smoke extracts. J Allergy Clin Immunol 2000;106:280–287.


Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50