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Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment

Abstract

A pattern of aberrations in the T-cell cytokine system that is typical for autoimmune disorders has also been reported in patients with schizophrenia, namely a decreased interleukin-2 (IL-2) production and increased levels of the soluble IL-2 receptor (sIL-2R). It has also been reported that the production of interferon-γ (IFN-γ) may be lowered. In a longitudinal design, we studied the production of both IFN-γ and IL-2 and their correlation in patients with schizophrenia during treatment and investigated whether associations exist between cytokine production and clinical variables. The production of IFN-γ and IL-2 was measured in equal numbers (n = 29) of patients with schizophrenia (DSM-IV) and controls who were matched for age and gender. Patients were measured 1 day after admission (T1), after 14 (T2) and 28 (T2) days of treatment. Psychopathology was assessed after these times. The production of both IFN-γ and IL-2 was significantly lower in patients than in controls throughout the whole investigation period (T1–T3). The productions of both cytokines were significantly correlated in controls (r = 0.60, P ≤ 0.001) as well as in patients with schizophrenia (mean production T1–T3: r = 0.71, P ≤ 0.001). No associations between cytokine measurements and psychopathology or age-at-onset could be found. Our findings of lowered and correlated IFN-γ and IL-2 production indicate that alterations in the cytokine system of patients with schizophrenia might resemble those in autoimmune disorders. It is suggested that these immunological abnormalities are associated with acute exacerbation, rather than with a clinical subtype of schizophrenia.

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References

  1. Lehmann-Facius H . Liquoruntersuchungen bei destruktiven Erkrankungen des Nervensystems, besonders bei Schizophrenien Neurol Psychiatrie 1937; 157: 109–115

    Article  Google Scholar 

  2. Ganguli R, Brar JS, Chengappa KNR, Yang ZW, Nimgaonkar VL, Rabin BS . Autoimmunity in schizophrenia Ann Med 1993; 25: 489–496

    Article  CAS  PubMed  Google Scholar 

  3. Kroemer G, Martinez C . Cytokines and autoimmune disease Clin Immunol Immunopathol 1991; 61: 275–295

    Article  CAS  PubMed  Google Scholar 

  4. Ruschen S, Stellberg W, Warnatz H . Kinetics of cytokine secretion by mononuclear cells of the blood from rheumatoid patients are different from those of healthy controls Clin Exp Immunol 1992; 89: 32–37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sanders ME, Makoba MW, Sharrow SO, Stephany D, Springer TA, Young HA et al. Human memory T-lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2 and LFA-1) and three other molecules (UCHL-1, Cdw29 and Pgp-1) and have enhanced interferon-gamma production J Immunol 1988; 140: 1401–1407

    CAS  PubMed  Google Scholar 

  6. Bruce LC, Peebles AMS . Clinical and experimental observations on catatonia J Ment Sci 1903; 49: 614–628

    Article  Google Scholar 

  7. Kirch DG . Infection and autoimmunity as etiologic factors in schizophrenia: a review and reappraisal Schizophr Bull 1993; 19: 355–370

    Article  CAS  PubMed  Google Scholar 

  8. Villemain F, Chatenoud L, Guillibert E, Pelicier Y, Bach JF . Decreased production of interleukin-2 in schizophrenia Ann NY Acad Sci 1987; 469: 669–675

    Article  Google Scholar 

  9. Kolyaskina GI, Morozov TP, Sekirina TP, Burbayeya GS . Immunological and Virological Studies in Schizophrenia. Presented at the Second World Congress on Viruses, Immunity, and Mental Health, October 6, 1988, Quebec

  10. Villemain F, Chatenoud L, Galinowski A, Homo-Delarche F, Ginestet D, Loo H et al. Aberrant T-cell mediated immunity in untreated schizophrenic patients: deficient interleukin-2 production Am J Psychiatry 1989; 146: 609–616

    Article  CAS  PubMed  Google Scholar 

  11. Ganguli R, Rabin BS, Belle SH . Decreased interleukin-2 production in schizophrenic patients Biol Psychiatry 1989; 26: 427–430

    Article  CAS  PubMed  Google Scholar 

  12. Sirota P, Fishman P, Elizur A, Djaldetty M . Lymphokine production in schizophrenic patients Biol Psychiatry 1990; 27: 173A

    Article  Google Scholar 

  13. 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

    Article  CAS  PubMed  Google Scholar 

  14. Hornberg M, Arolt V, Wilke I, Kruse A, Kirchner H . Lymphokine production in leukocyte cultures of patients with schizophrenia Schizophr Res 1995; 15: 237–242

    Article  CAS  PubMed  Google Scholar 

  15. Wilke I, Arolt V, Hornberg M, Kirchner H . Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenics Eur Arch Psychiatry Clin Neurosci 1996; 246: 279–284

    Article  CAS  PubMed  Google Scholar 

  16. Licinio J, Seibyl JP, Altemus M, Charney DS, Krystal JH . Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients Am J Psychiatry 1993; 150: 1408–1410

    Article  CAS  PubMed  Google Scholar 

  17. McAllister CG, van Kammen DP, Rehn TJ, Miller AL, Gurklis J, Kelley ME et al. Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status Am J Psychiatry 1995; 152: 1291–1297

    Article  CAS  PubMed  Google Scholar 

  18. Ganguli R, Rabin BS . Increased serum interleukin-2 receptor in schizophrenic and brain damaged subjects Arch Gen Psychiatry 1989; 46: 292

    Article  CAS  PubMed  Google Scholar 

  19. Rapaport MH, McAllister CG, Pickar D, Nelson DL, Paul SM . Elevated levels of soluble interleukin-2 receptors in schizophrenia Arch Gen Psychiatry 1989; 46: 291–292

    Article  CAS  PubMed  Google Scholar 

  20. Preble OT, Torrey EF . Serum interferon in patients with psychosis Am J Psychiatry 1985; 142: 1184–1186

    Article  CAS  PubMed  Google Scholar 

  21. Schindler L, Leroux M, Beck J, Moises HW, Kirchner H . Studies of cellular immunity, serum interferon titers, and natural killer cell activity in schizophrenic patients Acta Psychiatr Scand 1986; 73: 651–657

    Article  CAS  PubMed  Google Scholar 

  22. Becker D, Kritschmann E, Floru S, Shlomo-David Y, Gotlieb-Stematsky T . Serum interferon in first psychotic attack Br J Psychiatry 1990; 157: 136–138

    Article  CAS  PubMed  Google Scholar 

  23. Gattaz WF, Dalgalarrondo P, Schröder HC . Abnormalities in serum concentrations of interleukin-2 and interferon-γ in schizophrenia not detected Schizophr Res 1992; 6: 237–241

    Article  CAS  PubMed  Google Scholar 

  24. Ahokas A, Rimon R, Koskemieni M, Vaheri A, Julkunen I, Sarna S . Viral antibodies and interferon in acute psychiatric disorders J Clin Psychiatry 1987; 48: 194–196

    CAS  PubMed  Google Scholar 

  25. Katila H, Cantell K, Hirvonen S, Rimon R . Production of interferon alpha and gamma by lymphocytes from patients with schizophrenia Schizophr Res 1989; 2: 361–365

    Article  CAS  PubMed  Google Scholar 

  26. Cazzullo CL, Scarone S, Grassi B, Vismara C, Trabattoni D, Clerici M et al. Cytokines production in chronic schizophrenia patients with or without paranoid behaviour Prog Neuropsychopharmacol Biol Psychiatry 1998; 22: 947–957

    Article  CAS  PubMed  Google Scholar 

  27. Moises HW, Schindler L, Leroux M, Kirchner H . Decreased production of interferon-gamma in leucocyte cultures of schizophrenic patients Acta Psychiat Scand 1985; 72: 45–50

    Article  CAS  PubMed  Google Scholar 

  28. Kirchner H, Kleinicke C, Diegel W . A whole blood technique for testing production of human interferon by leukocytes Immunol Meth 1982; 48: 213–219

    Article  CAS  Google Scholar 

  29. Rothermundt M, Arolt V, Weitzsch C, Eckhoff D, Kirchner H . Production of cytokines in acute schizophrenic psychosis Biol Psychiatry 1996; 40: 1294–1297

    Article  CAS  PubMed  Google Scholar 

  30. Arolt V, Weitzsch C, Wilke I, Nolte A, Pinnow M, Kirchner H . Production of interferon-gamma in families with multiple occurrence of schizophrenia Psychiatry Res 1997; 66: 145–151

    Article  CAS  PubMed  Google Scholar 

  31. Arolt V, Weitzsch C . Rothermundt M, Eckhoff D, Kirchner H. Interferon-gamma in schizophrenia Adv Biol Psychiatry 1997; 18: 57–66

    Article  Google Scholar 

  32. Overall JE, Gorham DR . The Brief Psychiatric Rating Scale Psychol Rep 1962; 10: 799–812

    Article  Google Scholar 

  33. Kay SR, Fishbein A, Oppler LA . The Positive and Negative Syndrom Scale (PANSS) for schizophrenia Schizophr Bull 1987; 13: 261–276

    Article  CAS  PubMed  Google Scholar 

  34. Zier KS, Leo MM, Spielman RS, Baker L . Decreased synthesis of interleukin-2 (IL-2) in insulin-dependent diabetes mellitus Diabetes 1984; 33: 552–555

    Article  CAS  PubMed  Google Scholar 

  35. Roncarolo MG, Zoppo M, Bacchetta R, Gabbiano C, Sacchetti C, Cerutti F et al. Interleukin-2 production and interleukin-2 receptor expression in children with newly diagnosed diabetes Clin Immunol Immunopathol 1988; 49: 53–62

    Article  CAS  PubMed  Google Scholar 

  36. Kaye WA, Adri MN, Soeldner JS, Rabinowe SL, Kaldany A, Kahn CR et al. Aquired defect of interleukin-2 production in patients with type I diabetes mellitus N Engl J Med 1986; 315: 920–924

    Article  CAS  PubMed  Google Scholar 

  37. Catheley GB, Amor B, Fournier C . Defective IL-2 production in active rheumatoid arthritis: regulation by radiosensitive suppressor cells Clin Rheumatol 1986; 5: 482–492

    Google Scholar 

  38. Jokinen EI, Mottonen TT, Hannonen PJ, Arvilommi HS . Association of in vitro immune functions with the severity of the disease in rheumatoid arthritis Br J Rheumatol 1993; 32: 550–555

    Article  CAS  PubMed  Google Scholar 

  39. Steiner G, Studnicka-Benke A, Witzmann G, Hofler E, Smolen J . Soluble receptors for tumor necrosis factor and interleukin-2 in serum and synovial fluid of patients with rheumatoid arthritis, reactive arthritis and osteoarthritis J Rheumatol 1995; 22: 406–412

    CAS  PubMed  Google Scholar 

  40. Cuadrado MJ, Marubayashi M, Ortega C, Fernandez-Arcas N, Garcia-Cozar F, Pena J et al. Relationship of IL-2, IL-2R (CD25+), soluble IL-2R, and IL-4 with disease activity in SLE patients Lupus 1993; 2: 257–260

    Article  CAS  PubMed  Google Scholar 

  41. Kucharz EJ, Sierakowski SJ, Goodwin JS . Lithium in vitro enhances interleukin-2 production by T cells from patients with systemic lupus erythematosus Immunopharmacol Immunotoxicol 1993; 15: 515–523

    Article  CAS  PubMed  Google Scholar 

  42. Samosonov MY, Tilz GP, Egorova O, Reibnegger G, Balabanova RM, Nassonov EL et al. Serum soluble markers of immune activation and disease activity in systemic lupus erythematosus Lupus 1995; 4: 29–32

    Article  Google Scholar 

  43. Suzuki T, Suzuki N, Engleman EG, Mitsushima Y, Sakane T . Low serum levels of dehydroepiandrosterone may cause deficient IL-2 production by lymphocytes in patients with systemic lupus erythematosus Clin Exp Immunol 1995; 99: 251–255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Corrales JJ, Orfao A, Lopez A, Mories MT, Miralles JM, Ciudad J . Analysis of IL-2 and IL-6 binding to peripheral blood lymphocytes in Graves’ disease. Relationship with disease activity Cytometr 1997; 30: 118–123

    Article  CAS  Google Scholar 

  45. Eisenstein Z, Engelsman E, Weiss M, Kalechman Y, Sredni B . Modulation of the IL-2 production defect in vitro in Graves’ disease Clin Exp Immunol 1994; 96: 323–328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Navikas V, Link H . Review: cytokines and the pathogenesis of multiple sclerosis J Neurosci Res 1996; 45: 322–333

    Article  CAS  PubMed  Google Scholar 

  47. Selmaj K, Nowak Z, Tchorzewski H . Interleukin-1 and interleukin-2 production by peripheral blood mononuclear cells in multiple sclerosis patients J Neurol Sci 1988; 85: 67–76

    Article  CAS  PubMed  Google Scholar 

  48. Wandinger KP, Wessel K, Neustock P, Siekhaus A, Kirchner H . Diminished production of type I interferon and interleukin-2 in patients with multiple sclerosis J Neurol Sci 1997; 149: 87–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hartung HP, Reiners K, Schmidt B, Stoll G, Toyka KV . Serum interleukin-2 concentrations in Guillain-Barré syndrome and chronic ideopathic demyelinating polyradiculoneuropathy: comparison with other neurological diseases of presumed immunopathogenesis Ann Neurol 1991; 30: 48–53

    Article  CAS  PubMed  Google Scholar 

  50. Zoukos Y, Kidd D, Woodroofe MN, Kendall BE, Thompsom AJ, Cuzner ML . Increased expression of high affinity IL-2 receptors and beta-adrenoreceptors on peripheral blood mononuclear cells is associated with clinical and MRI activity in multiple sclerosis Brain 1994; 117: 307–315

    Article  PubMed  Google Scholar 

  51. Ciampolillo A, Guastamachia E, Caragiulo L, Lollino G, DeRobertis O, Lattanzi V et al. In vitro secretion of interleukin-1 beta and interferon-gamma by peripheral blood lymphomononuclear cells in diabetic patients Diabetes Res Clin Prac 1993; 21: 87–93

    Article  CAS  Google Scholar 

  52. Vonherrath MG, Oldstone MBA . Interferon gamma is essential for destruction of beta cells and development of insulin-dependent diabetes mellitus J Exp Med 1997; 185: 531–539

    Article  CAS  Google Scholar 

  53. Baldeon ME, Neece DJ, Nandi D, Monaco JJ, Gaskins HR . Interferon gamma independently activates the MHC class I antigen processing pathway and diminishes glucose responsiveness in pancreatic cell lines Diabetes 1997; 46: 770–778

    Article  CAS  PubMed  Google Scholar 

  54. Zangerle PF, DeGroote D, Lopez M, Meuleman RJ, Vrindts Y, Fauchet F et al. Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma, and GM-CSF) in whole blood: II. Application to rheumatoid arthritis and osteoarthritis Cytokine 1992; 4: 568–575

    Article  CAS  PubMed  Google Scholar 

  55. Gattorno M, Facchetti P, Ghiotto F, Vignola S, Buoncompagni A, Prigione I et al. Synovial fluid T cell clones from oligoarthricular juvenile arthritis patients display a prevalent TH1/TH0-type pattern of cytokine secretion irrespective of immunophenotype Clin Exp Immunol 1997; 109: 4–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dolhain RJEM, Vanderheiden AN, Terhaar NT, Breedveld FC, Miltenburg AMM . Shift towards T-lymphocytes with a T-helper1 cytokine secretion profile in the joints of patients with rheumatoid arthritis Arthritis Rheumatism 1996; 39: 1961–1969

    Article  CAS  PubMed  Google Scholar 

  57. Olsson T . Cytokine-producing cells in experimental autoimmune encephalomyelitis and multiple sclerosis Neurology 1995; 45: (suppl 6) 11–15

    Article  Google Scholar 

  58. Beck J, Rondot P, Catinot L, Falcoff L, Kirchner H, Wietzerbin J . Increased production of interferon gamma and tumor necrosis factor precedes clinical manifestation in multiple sclerosis: do cytokines trigger off exacerbations? Acta Neurol Scand 1988; 78: 318–323

    Article  CAS  PubMed  Google Scholar 

  59. Merrill J, Jonakait GM . Interactions of the nervous and immune systems in development, normal brain homeostasis, and disease FASEB J 1995; 9: 611–618

    Article  CAS  PubMed  Google Scholar 

  60. Jonakait GM . Interferon-gamma promotes cholinergic differentiation of embrionic septal nuclei and adjacent basal forebrain Neuron 1995; 12: 1149–1159

    Google Scholar 

  61. Nistico G, DeSarro G . Is interleukin-2 a neuromodulator in the brain? Trends Neurosci 1991; 14: 146–150

    Article  CAS  PubMed  Google Scholar 

  62. Alonso R, Chaudieu I, Diorio J, Krishnamurthy A, Quirion R, Boksa P . Interleukin-2 modulates evoked release of 3H-dopamine in rat cultured mesencephalic cells J Neurochem 1993; 61: 1284–1290

    Article  CAS  PubMed  Google Scholar 

  63. Lapchak PA . A role for interleukin-2 in the regulation of striatal dopaminergic function Neuro Report 1992; 3: 165–168

    CAS  Google Scholar 

  64. Pasternak KI, Timo-Iara C, Rodrigues CJ, Maria DA, Duarte AJS, Paiva L et al. Circumscribed lesion of the medial forebrain bundle area causes structural impairment of lymphoid organs and severe depression of immune function in rats Mol Psychiatry 1998; 3: 397–404

    Article  CAS  PubMed  Google Scholar 

  65. Claret E, Renversez J-C, Zheng X, Bonnefoix T, Sotto J-J . Valid estimation of IL-2 secretion by PHA-stimulated T-cell clones absolutely requires the use of anti-CD25 monoclonal antibody to prevent IL-2 consumption Immunol Lett 1992; 33: 179–186

    Article  CAS  PubMed  Google Scholar 

  66. Rapaport MH, Torrey EF, McAllister CG, Nelson DL, Pickar D, Paul SM . Increased serum interleukin-2 receptors in schizophrenic monozygotic twins Eur Arch Psychiatr Clin Neurosci 1993; 242: 7–10

    Article  Google Scholar 

  67. Ganguli R, Brar JS, Chengappa KNR, DeLeo M, Yang ZW, Shurin G et al. Mitogen-stimulated interleukin-2 production in never-medicated, first episode schizophrenic patients Arch Gen Psychiatry 1995; 52: 668–671

    Article  CAS  PubMed  Google Scholar 

  68. Rothermundt M, Arolt V, Weitzsch C, Eckhoff D, Kirchner H . Immunological dysfunction in schizophrenia: a systematic approach Neuropsychobiology 1998; 37: 186–193

    Article  CAS  PubMed  Google Scholar 

  69. McAllister CG . Rapaport MH, Pickar D, Paul SM. Effects of short-term administration of antipsychotic drugs on lymphocite subsets in schizophrenic patients Arch Gen Psychiatry 1989; 46: 956–957

    Article  CAS  PubMed  Google Scholar 

  70. Müller N, Ackenheil M, Hofschuster E, Mempel W, Eckstein R . Cellular immunity in schizophrenic patients before and during neuroleptic treatment Psychiatry Res 1991; 37: 147–160

    Article  PubMed  Google Scholar 

  71. Rapaport MH, Lohr JB . Serum soluble interleukin-2 receptors in neuroleptic naive schizophrenic subjects and in medicated subjects with and without tardive dyskinesia Psychiatr Scand 1994; 90: 311–315

    Article  CAS  Google Scholar 

  72. Leykin I, Mayer R, Shinitzky M . Short and long-term immunosuppressive effects of clozapine and haloperidol Immunopharmacology 1997; 37: 75–86

    Article  CAS  PubMed  Google Scholar 

  73. Hinze-Selch D, Becker EW, Stein GM, Berg PA, Mullington J, Holsboer F et al. Effects of clozapine on in vitro immune parameters: a longitudinal study in clozapine-treated schizophrenic patients Neuropsychopharmacology 1998; 19: 114–122

    Article  CAS  PubMed  Google Scholar 

  74. Pollmächer T, Hinze-Selch D, Mullington J, Holsboer F . Clozapine-induced increase in plasma levels of soluble interleukin-2 receptors (letter) Arch Gen Psychiatry 1995; 52: 877

    Article  PubMed  Google Scholar 

  75. Ganguli R, Brar JS, Rabin BS . Clozapine-induced increase in plasma levels of soluble interleukin-2 receptors (comment) Arch Gen Psychiatry 1995; 52: 878

    Article  Google Scholar 

  76. Sasaki T, Nanko S, Fukuda R, Kawate T, Kunugi H, Kazamatsuri H . Changes of immunological functions after acute exacerbation in schizophrenia Biol Psychiatry 1994; 35: 173–178

    Article  CAS  PubMed  Google Scholar 

  77. Gudewill S, Pollmacher T, Vedder H, Schreiber W, Fassbender K, Holsboer F . Nocturnal plasma levels of cytokines in healthy men Eur Arch Psychiatry Clin Neurosci 1992; 242: 53–56

    Article  CAS  PubMed  Google Scholar 

  78. Uthgenannt D, Schoolmann D, Pietrowsky R, Fehm HL, Born J . Effects of sleep on the production of cytokines in humans Psychosom Med 1995; 57: 97–104

    Article  CAS  PubMed  Google Scholar 

  79. Irwin M, Thompson J, Miller C, Gillin JC, Ziegler M . Effects of sleep and sleep deprivation on catecholamine and interleukin-2 levels in humans: clinical implications J Clin Endocrinol Metab 1999; 84: 1979–1985

    CAS  PubMed  Google Scholar 

  80. Appelberg B, Katila H, Rimon R . Plasma interleukin-1 beta and sleep architecture in schizophrenia and other nonaffective psychoses Psychosom Med 1997; 59: 529–532

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the Stiftung Volkswagenwerk (Volkswagenwerk Science Foundation, No. I 71/998). We are grateful to Dörthe Eckhoff, MD and Christine Weitzsch, MD for their help with the patient recruitment and the laboratory work.

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Arolt, V., Rothermundt, M., Wandinger, KP. et al. Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment. Mol Psychiatry 5, 150–158 (2000). https://doi.org/10.1038/sj.mp.4000650

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