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Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia

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Abstract

The cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6) increase during immune activation, they are released from activated astrocytes and microglial cells in the central nervous system (CNS), and they are able to enhance the catecholaminergic neurotransmission. This study focused on the soluble receptors of IL-2 and IL-6 (sIL-2R, sIL-6R) as a part of the regulation system of IL-2 and IL-6. We studied serum levels of sIL-2R in 30 schizophrenic patients not under neuroleptic medication during an acute exacerbation of the disease and reexamined these patients under neuroleptic treatment after clinical improvement. The SIL-6R levels of 39 schizophrenic patients were estimated under the same conditions. The results were compared with the levels of sIL-2R and sIL-6R in 42 healthy controls. No difference was found between the schizophrenic patients before neuroleptic treatment and the healthy controls. During neuroleptic treatment, however, there was a significant increase of sIL-2R levels and a significant decrease of the sIL-6R levels between the pre- and post-conditions. In comparison with healthy controls, the treatment group also showed increased sIL-2R levels and decreased sIL-6R levels. These results suggest that treatment with neuroleptics is associated with increased sIL-2R and decreased sIL-6R. Since sIL-2R bind and inactivate IL-2, whereas sIL-6R form an active complex with IL-6, the increase of sIL-2R and the decrease of sIL-6R together may reflect a functional down regulation of these activating cytokines. This suggests that neuroleptic therapy has a differentiated immunomodulatory effect.

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References

  • American Psychiatric Association (1990) Structured clinical interview for DSM-III-R. American Psychiatric Press, Washington DC

    Google Scholar 

  • American Psychiatric Association (1987) Diagnostic and statistical manual of mental disorders (DSM-III-R), 3rd edn, revised. American Psychiatric Press, Washington DC

    Google Scholar 

  • Baker GA, Syntalo R, Blumenstein J (1977) Effects of psychotropic agents upon the blastogenic response on human T-lymphocytes. Biol Psychiatry 12: 159–169

    PubMed  CAS  Google Scholar 

  • Banks WA, Kastin AJ (1992) The interleukins-1 alpha, -1 beta, and -2 do not acutely disrupt the murine blood-brain barrier. Int J Immunopharmacol 14: 629–636

    Article  PubMed  CAS  Google Scholar 

  • Barral-Netto M, Barrai A, Santos SB, Carvalho EM, Badaro R, Rocha H, Reed SG, Johnson WD Jr (1991) Soluble IL-2 receptors as an agent of serum-mediated suppression in human visceral leishmaniasis. J Immunol 147: 281–284

    PubMed  CAS  Google Scholar 

  • Bessler H, Levental Z, Karp L, Modai I, Djaldetti M, Weizman A (1995) Cytokine production in drug-free and neuroleptictreated schizophrenic patients. Biol Psychiatry 38: 297–302

    Article  PubMed  CAS  Google Scholar 

  • Brivio S, Lissoni P, Mancini D, Tisi E, Tancini G, Barni S, Nociti V (1991) Effect of antitumor surgery on soluble interleukin-2 receptor serum levels. Am J Surg 161: 466–469

    Article  PubMed  CAS  Google Scholar 

  • Damle RN, Advani SH, Gangal SG (1992) Analysis of regulation of T-cell responses by soluble inhibitory factors from the sera of patients with Hodgkin’s disease. Int J Cancer 50: 192–196

    Article  PubMed  CAS  Google Scholar 

  • Denicoff KD, Rubinoff DR, Papa MZ, Simpson C, Seipp CA, Lotze MT, Chang AE, Rosenstein D, Rosenberg SA (1987) The neuropsychiatric effects of treatment with Interleukin-2 and lymphokine-activated killer cells. Ann Intern Med 107: 293–300

    PubMed  CAS  Google Scholar 

  • Gallien M, Schnetzler JP, Morin J (1977) Antinuclear antibodies and lupus cells in 600 hospitalized phenothiazine treated patients. Ann Med Psychol Med 1: 237–248

    Google Scholar 

  • Ganguli R, Rabin BS (1989) Increased serum Interleukin 2 receptor levels in schizophrenic and brain damaged subjects. Arch Gen Psychiatry 46: 292

    PubMed  CAS  Google Scholar 

  • Ganguli R, Yang Z, Shurin G, Chengappa R, Brar JS, Gubbi AV, Rabin BS (1994) Serum Interleukin-6 concentration in schizophrenia: elevation associated with duration of illness. Psychiatry Res 51: 1–10

    Article  PubMed  CAS  Google Scholar 

  • Ganguli R, Brar JS, Chengappa KR, DeLeo M, Yang ZW, Shurin G, Rabin B (1995a) Mitogen-stimulated interleukin 2 production in never-medicated, first episode schizophrenics: the influence of age of onset and negative symptoms. Arch Gen Psychiatry 52: 878

    Google Scholar 

  • Ganguli R, Brar JS, Rabin BS (1995b) Reply on: Pollmächer T et al. Clozapine-induced increase in plasma levels of soluble interleukin-2 receptors. Arch Gen Psychiatry 52: 668–672

    PubMed  CAS  Google Scholar 

  • Hama T, Kushima Y, Miyamoto M, Kubota M, Takei N, Hatanaka H (1991) Interleukin-6 improves the survival of mesencephalic catecholaminergic and septal cholinergic neurons from postnatal, two-week-old rats in cultures. Neuroscience 40: 445–452

    Article  PubMed  CAS  Google Scholar 

  • Hornberg M, Arolt V, Wilke I, Kruse A, Kirchner H (1995) Production of interferons and lymphokines in leukocyte cultures of patients with schizophrenia. Schizophr Res 15: 237–242

    Article  PubMed  CAS  Google Scholar 

  • Hornung N, Raskova J, Raska K, Degiannis D (1992) I1-2 responsiveness of lectin-induced lymphoblasts: soluble IL-2 receptor release and differential in vitro effects of immunosuppressants. Int J Immunopharmacol 14: 753–760

    Article  PubMed  CAS  Google Scholar 

  • Kay SR, Oppler LA, Fiszbein A (1986) Positive and negative syndrome scale (PANSS) manual. Multi-Health Systems, North Tonawanda, New York

    Google Scholar 

  • Licinio J, Seibyl JP, Altemus M, Charney DS, Krystal JH (1993) Elevated levels of Interleukin-2 in neuroleptic-free schizophrenics. Am J Psychiatry 150: 1408–1410

    PubMed  CAS  Google Scholar 

  • Mackiewicz A, Schooltink H, Heinrich PC, Rose-John S (1992) Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins. J Immunol 49: 2021–2027

    Google Scholar 

  • Maes M, Meltzer HY, Bosnians E (1994) Immune-inflammatory markers in schizophrenia: comparison to normal controls and effects of clozapine. Acta Psychiatr Scand 89: 346–351

    Article  PubMed  CAS  Google Scholar 

  • Maes M, Bosnians E, Ranjan R, Vandoolaeghe B, Meltzer HY, Ley M de, Berghmans R, Stans G, Desnyder R (1996) Lower plasma CC16, a natural anti-inflammatory protein, and increased plasma interleukin-1 receptor antagonist in schizophrenia: effects of antipsychotic drugs. Schizophr Res 21: 39–50

    Article  PubMed  CAS  Google Scholar 

  • McAllister CG, Rapaport MH, Pickar D, Paul SM (1989) Effect of short-term administration of antipsychotic drugs on lymphocyte subsets in schizophrenic patients. Arch Gen Psychiatry 46: 956–957

    PubMed  CAS  Google Scholar 

  • McAllister CG, van Kämmen DP, Rehn TJ, Miller AL, Gurklis J, Kelley ME, Yao J, Peters JL (1995) Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am J Psychiatry 152: 1291–1297

    PubMed  CAS  Google Scholar 

  • Müller N, Ackenheil M (1995) Immunoglobulin and albumin contents of cerebrospinal fluid in schizophrenic patients: the relationship to negative symptomatology. Schizophr Res 14: 223–228

    Article  PubMed  Google Scholar 

  • Müller N (1997) The role of the cytokine network in the CNS and psychic disorders. Nervenarzt 68: 11–20

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Müller N, Empel M, Putz A, Schwarz M, Ackenheil M (1997a) Immunological effects of treatment in schizophrenia. In: Henneberg AE, Kaschka WP (eds) Immunological alterations in psychiatric diseases. Karger, Basel, pp 78–84

    Chapter  Google Scholar 

  • Müller N, Dobmeier P, Empel M, Riedel M, Schwarz M, Ackenheil M (1997b) Soluble IL-6 Receptors in the serum and cerebrospinal fluid of paranoid schizophrenic patients. Eur Psychiatry 12: 294–299

    Article  PubMed  Google Scholar 

  • Müller N, Hadjamu M, Riedel M, Primbs J, Ackenheil M, Gruber R (submitted) The adhesion-molecule receptor expression on T helper cells increases during treatment with neuroleptics and is related to the blood-brain barrier permeability in schizophrenia. Am J Psychiatry

  • Norris JG, Benveniste EN (1993) Interleukin-6 production by astrocytes: induction by the neurotransmitter norepinephrine. J Neuroimmunol 45: 137–146

    Article  PubMed  CAS  Google Scholar 

  • Plata-Salaman CR (1991) Immunoregulators in the nervous system. Neurosci Behav Rev 15: 185–215

    CAS  Google Scholar 

  • Plata-Salaman CR, Ffrench-Mullen JM (1993) Interleukin-2 modulates calcium currents in dissociated hippocampal CA1 neurons. Neuroreport 4: 579–581

    Article  PubMed  CAS  Google Scholar 

  • Pollmächer T, Hinze-Selch D, Mullington J, Holsboer F (1995) Clozapine-induced increase in plasma levels of soluble Interleukin-2 receptors. Arch Gen Psychiatry 52: 877–878

    PubMed  Google Scholar 

  • Ransohoff RM, Benveniste EN (1996) Cytokines and the CNS. CNC Press NY, London

    Google Scholar 

  • Rapaport MH, McAllister CG, Pickar D, Nelson DM, Paul SM (1989) Elevated levels of soluble interleukin-2 receptors in schizophrenia. Arch Gen Psychiatry 46: 292

    Google Scholar 

  • Rapaport MH, McAllister CG, Kirch DG, Pickar D (1990) The effects of typical and atypical neuroleptics on mitogen-induced T lymphocyte responsiveness. Biol Psychiatry 29: 715–717

    Article  Google Scholar 

  • Rapaport MH, Doran AR, Nelson DM, McAllister CG, Magliozzi JR, Paul SM (1991) Haloperidol and soluble Interleukin-2 receptors. Biol Psychiatry 30: 1063–1065

    Article  PubMed  CAS  Google Scholar 

  • Rapaport MH, Torrey EF, McAllister CG, Nelson DM, Pickar D, Paul SM (1993) Increased serum soluble interleukin-2 receptors in schizophrenic monozygotic twins. Eur Arch Psychiatry Clin Neurosci 243: 7–10

    Article  PubMed  CAS  Google Scholar 

  • Rapaport MH, McAllister CG, Kim YS, Han JH, Pickar D, Nelson DM, Kirch DG, Paul SM (1994) Increased soluble Interleukin-2 receptors in Caucasian and korean schizophrenic patients. Biol Psychiatry 35: 767–771

    Article  PubMed  CAS  Google Scholar 

  • Reiber H, Felgenhauer K (1987) Protein transfer at the blood cerebrospinal fluid barrier and the quantitation of the humoral immune response within the central nervous system. Clin Chem Acta 163: 319–328

    Article  CAS  Google Scholar 

  • Russo R, Ciminale M, Ditommaso S, Siliquini R, Zotti C, Ruggenini AM (1994) Hepatitis B vaccination in psychiatric patients. Lancet I 343: 394

    Article  Google Scholar 

  • Saunders JC, Muchmore E (1964) Phenothiazine effect on human antibody synthesis. Br J Psychiatry 110: 84–89

    Article  PubMed  CAS  Google Scholar 

  • Sawada M, Suzumura A, Marunouchi T (1992) TNF-alpha induces IL-6 production by astrocytes, but not by microglia. Brain Res 583: 296–299

    PubMed  CAS  Google Scholar 

  • Schleuning MJ, Duggan A, Reem GH (1989) Inhibition by chlorpromazine of lymphokine-specific mRNA expression in human thymocytes. Eur J Immunol 19: 1491–1496

    Article  PubMed  CAS  Google Scholar 

  • Schleuning M, Brumme V, Wilmanns W (1994) Inhibition of cyclosporin A/FK 506 resistant, lymphokine-induced T-cell activation by phenothiazine derivates. Naunyn-Schmiedeberg’s Arch Pharmacol 350: 100–103

    Article  CAS  Google Scholar 

  • Schöbitz B, Pezeshki G, Pohl T, Hermann U, Heinrich PC, Holsboer F, Reul JM (1995) Soluble interleukin-6 (IL-6) receptor augments central effects of IL-6 in vivo. FASEB J 9: 659–664

    PubMed  Google Scholar 

  • Smith RS (1991) Is schizophrenia caused by excessive production of interleukin-2 and interleukin-2 receptors by gastrointestinal lymphocytes? Med Hypotheses 34: 225–229

    Article  PubMed  CAS  Google Scholar 

  • Smith RS (1992) A comprehensive macrophage-T-lymphocyte theory of schizophrenia. Med Hypotheses 39: 248–257

    Article  PubMed  CAS  Google Scholar 

  • Tibbling G, Link H, Ohmann S (1977) Principles of albumin and IgG analyses in neurological disorders. I: Establishment of reference values. Scand J Clin Lab Invest 37: 385–390

    Article  PubMed  CAS  Google Scholar 

  • Villemain F, Chatenoud L, Galinowski A, Homo-Delarche F, Genestet D, Loo H, Zarifarain E, Bach JF (1989) Aberrant T-cellmediated immunity in untreated schizophrenic patients: deficient interleukin-2 production. Am J Psychiatry 146: 609–616

    PubMed  CAS  Google Scholar 

  • Waguespack PJ, Banks WA, Kastin AJ (1994) Interleukin-2 does not cross the blood-brain barrier by a saturable transport system. Brain Res Bull 34: 103–109

    Article  PubMed  CAS  Google Scholar 

  • Wilke I, Arolt V, Rothermundt M, Weitzsch Ch, Hornberg M, Kirchner H (1996) Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 246: 279–284

    Article  PubMed  CAS  Google Scholar 

  • Zalcman S, Green-Johnson JM, Murray L, Nance DM, Dyck D, Anisman H, Greenberg AH (1994) Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6. Brain Res 643: 40–49

    Article  PubMed  CAS  Google Scholar 

  • Zarrabi MH, Zucker S, Miller F, Derman RM, Romeno GS, Hartnett JA, Varma AO (1979) Immunologic and coagulation disorders in chlorpromazine-treated patients. Ann Int Med 91: 194–199

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Psychiatric Hospital, Ludwig Maximilian University, Nußbaumstrasse 7, D-80336, Munich, Germany

    Norbert Müller, Monika Empl, Michael Riedel, Markus Schwarz & Manfred Ackenheil

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  1. Norbert Müller
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  2. Monika Empl
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  3. Michael Riedel
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  4. Markus Schwarz
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  5. Manfred Ackenheil
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Müller, N., Empl, M., Riedel, M. et al. Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia. Eur Arch Psychiatry Clin Neurosci 247, 308–313 (1997). https://doi.org/10.1007/BF02922260

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  • DOI: https://doi.org/10.1007/BF02922260

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