Abstract
Aberrant activation of the immune system has been implicated in an increasingly large number of disease states and can influence cognition, mood, and memory. There is a long and controversial history of reports of immune activation associated with schizophrenia. In this study, we measured mitogen-stimulated cytokine levels serially in 100 medication-stabilized continuously ill subjects with schizophrenia and compared and contrasted them with mitogen-stimulated cytokine levels from 51 normal volunteers. The subjects with schizophrenia had consistently higher mitogen-stimulated IL-2 levels and lower IL-6 levels than the normal volunteers. These effects could not be explained by medications, smoking, or other clinical variables. We conclude that continuously symptomatic medication-stabilized subjects with schizophrenia have a mitogen-stimulated cytokine expression pattern that is suggestive of ongoing immune activation.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
American Psychiatric Association (1994). The Diagnostic and Statistical Manual of Mental Disorders. DSM-IV: Washington, DC.
Arolt V, Rothermundt M, Wandinger KP, Kirchner H (2000). Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood of patients with schizophrenia during treatment. Mol Psychiatry 5: 150–158.
Bessler H, Levental Z, Karp L, Modai I, Djaldetti M, Weizman A (1995). Cytokine production in drug-free and neuroleptic-treated schizophrenic patients. Biol Psychiatry 38: 297–302.
Cazzullo CL, Sacchetti E, Galluzzo A, Panariello A, Adorni A, Pegoraro M et al (2002). Cytokine profiles in schizophrenic patients treated with risperidone: a 3-month follow-up study. Prog Neuropsychopharmacol Biol Psychiatry 26: 33–39.
Cazzullo CL, Sacchetti E, Galluzzo A, Panariello A, Colombo F, Zagliani A et al (2001). Cytokine profiles in drug-naive schizophrenic patients. Schizophr Res 47: 293–298.
Cheng SM, Lai JH, Yang SP, Tsao TP, Ho LJ, Liou JT et al (2008). Modulation of human T cells signaling transduction by lovastatin. Int J Cardiol. 27 Nov 2008 (e-pub ahead of print).
De Groote D, Zangerle PF, Gevaert Y, Fassotte MF, Beguin Y, Noizat-Pirenne F et al (1992). 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 4: 239–248.
Dunn AJ (2006). Effects of cytokines and infections on brain neurochemistry. Clin Neurosci Res 6: 52–68.
First MB (1997). Structured Clinical Interview for DSM-IV Axis I Disorders: SCID-I. American Psychiatric Press: Washington, DC.
Ganguli R, Brar JS, Chengappa KR, DeLeo M, Yang ZW, Shurin G et al (1995). Mitogen-stimulated interleukin-2 production in never-medicated, first-episode schizophrenic patients. The influence of age at onset and negative symptoms. Arch Gen Psychiatry 52: 668–672.
Ganguli R, Rabin BS, Belle SH (1989). Decreased interleukin-2 production in schizophrenic patients. Biol Psychiatry 26: 427–430.
Giebelen IA, van Westerloo DJ, LaRosa GJ, de Vos AF, van der Poll T (2007). Local stimulation of alpha7 cholinergic receptors inhibits LPS-induced TNF-alpha release in the mouse lung. Shock 28: 700–703.
Haack M, Hinze-Selch D, Fenzel T, Kraus T, Kuhn M, Schuld A et al (1999). Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res 33: 407–418.
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.
Kay SR, Fiszbein A, Opler LA (1987). The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13: 261–276.
Kim DJ, Kim W, Yoon SJ, Go HJ, Choi BM, Jun TY et al (2001). Effect of risperidone on serum cytokines. Int J Neurosci 111: 11–19.
Kim YK, Lee MS, Suh KY (1998). Decreased interleukin-2 production in Korean schizophrenic patients. Biol Psychiatry 43: 701–704.
Kim YK, Myint AM, Lee BH, Han CS, Lee HJ, Kim DJ et al (2004). Th1, Th2 and Th3 cytokine alteration in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 28: 1129–1134.
Maes M, Bocchio Chiavetto L, Bignotti S, Battisa Tura G, Pioli R, Boin F et al (2000). Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics. Eur Neuropsychopharmacol 10: 119–124.
Maes M, Bosmans E, Kenis G, De Jong R, Smith RS, Meltzer HY (1997). In vivo immunomodulatory effects of clozapine in schizophrenia. Schizophr Res 26: 221–225.
Maes M, Meltzer HY, Bosmans E (1994). Immune-inflammatory markers in schizophrenia: comparison to normal controls and effects of clozapine. Acta Psychiatr Scand 89: 346–351.
Matsunaga K, Klein TW, Friedman H, Yamamoto Y (2001). Involvement of nicotinic acetylcholine receptors in suppression of antimicrobial activity and cytokine responses of alveolar macrophages to Legionella pneumophila infection by nicotine. J Immunol 167: 6518–6524.
McAfoose J, Baune BT (2009). Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev 33: 355–366.
Monteleone P, Fabrazzo M, Tortorella A, Maj M (1997). Plasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: effects of clozapine treatment. Psychiatry Res 71: 11–17.
Müller N, Empl M, Riedel M, Schwarz M, Ackenheil M (1997). Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia. Eur Arch Psychiatry Clin Neurosci 247: 308–313.
Müller N, Schwarz M (2006a). Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res 10: 131–148.
Müller N, Schwarz MJ (2006b). Neuroimmune-endocrine crosstalk in schizophrenia and mood disorders. Expert Rev Neurother 6: 1017–1038.
Müller N, Schwarz MJ (2007). The immunological basis of glutamatergic disturbance in schizophrenia: towards an integrated view. J Neural Transm Suppl 269–280.
Müller N, Schwarz MJ (2008). COX-2 inhibition in schizophrenia and major depression. Curr Pharm Des 14: 1452–1465.
Müller N, Ulmschneider M, Scheppach C, Schwarz MJ, Ackenheil M, Moller HJ et al (2004). COX-2 inhibition as a treatment approach in schizophrenia: immunological considerations and clinical effects of celecoxib add-on therapy. Eur Arch Psychiatry Clin Neurosci 254: 14–22.
Myint AM, Schwarz MJ, Steinbusch HW, Leonard BE (2009). Neuropsychiatric disorders related to interferon and interleukins treatment. Metab Brain Dis 24: 55–68.
Narayan S, Tang B, Head SR, Gilmartin TJ, Sutcliffe JG, Dean B et al (2008). Molecular profiles of schizophrenia in the CNS at different stages of illness. Brain Res. 18 Aug 2008 (e-pub ahead of print).
Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J et al (2005). Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 352: 29–38.
O'Donnell MC, Catts SV, Ward PB, Liebert B, Lloyd A, Wakefield D et al (1996). Increased production of interleukin-2 (IL-2) but not soluble interleukin-2 receptors (sIL-2R) in unmedicated patients with schizophrenia and schizophreniform disorder. Psychiatry Res 65: 171–178.
Pollmacher T, Hinze-Selch D, Fenzel T, Kraus T, Schuld A, Mullington J (1997). Plasma levels of cytokines and soluble cytokine receptors during treatment with haloperidol. Am J Psychiatry 154: 1763–1765.
Pollmacher T, Hinze-Selch D, Mullington J (1996). Effects of clozapine on plasma cytokine and soluble cytokine receptor levels. J Clin Psychopharmacol 16: 403–409.
Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E (2008). Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 63: 801–808.
Rapaport MH, Caligiuri MP, Lohr JB (1997). An association between increased serum-soluble interleukin-2 receptors and a disturbance in muscle force in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 21: 817–827.
Rapaport MH, Delrahim KK, Bresee CJ, Maddux RE, Ahmadpour O, Dolnak D (2005). Celecoxib augmentation of continuously ill patients with schizophrenia. Biol Psychiatry 57: 1594–1596.
Rapaport MH, Doran AR, Nelson DL, McAllister C, Magliozzi JR, Paul SM (1991a). Haloperidol and soluble interleukin-2 receptors. Biol Psychiatry 30: 1063–1064.
Rapaport MH, Lohr JB (1994). Serum-soluble interleukin-2 receptors in neuroleptic-naive schizophrenic subjects and in medicated schizophrenic subjects with and without tardive dyskinesia. Acta Psychiatr Scand 90: 311–315.
Rapaport MH, McAllister CG, Kim YS, Han JH, Pickar D, Nelson DL et al (1994). Increased serum soluble interleukin-2 receptors in Caucasian and Korean schizophrenic patients. Biol Psychiatry 35: 767–771.
Rapaport MH, McAllister CG, Kirch DG, Pickar D (1991b). The effects of typical and atypical neuroleptics on mitogen-induced T lymphocyte responsiveness. Biol Psychiatry 29: 715–717.
Rapaport MH, McAllister CG, Pickar D, Nelson DL, Paul SM (1989). Elevated levels of soluble interleukin 2 receptors in schizophrenia. Arch Gen Psychiatry 46: 291–292.
Rapaport MH, Torrey EF, McAllister CG, Nelson DL, Pickar D, Paul SM (1993). Increased serum soluble interleukin-2 receptors in schizophrenic monozygotic twins. Eur Arch Psychiatry Clin Neurosci 243: 7–10.
Rothermundt M, Arolt V, Leadbeater J, Peters M, Rudolf S, Kirchner H (2000). Cytokine production in unmedicated and treated schizophrenic patients. Neuroreport 11: 3385–3388.
Rothermundt M, Arolt V, Weitzsch C, Eckhoff D, Kirchner H (1998). Immunological dysfunction in schizophrenia: a systematic approach. Neuropsychobiology 37: 186–193.
Rubin RT, Poland RE, Lesser IM (1990). Neuroendocrine aspects of primary endogenous depression. X: Serum growth hormone measures in patients and matched control subjects. Biol Psychiatry 27: 1065–1082.
Stolina M, Sharma S, Lin Y, Dohadwala M, Gardner B, Luo J et al (2000). Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis. J Immunol 164: 361–370.
Stone TW, Behan WM (2007). Interleukin-1beta but not tumor necrosis factor-alpha potentiates neuronal damage by quinolinic acid: protection by an adenosine A2A receptor antagonist. J Neurosci Res 85: 1077–1085.
van Westerloo DJ, Giebelen IA, Florquin S, Bruno MJ, Larosa GJ, Ulloa L et al (2006). The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology 130: 1822–1830.
Villemain F, Chatenoud L, Guillibert E, Pelicier Y, Bach JF (1987). Decreased production of interleukin-2 in schizophrenia. Ann N Y Acad Sci 496: 669–675.
Wilke I, Arolt V, Rothermundt M, Weitzsch C, 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.
Wisse BE (2004). The inflammatory syndrome: the role of adipose tissue cytokines in metabolic disorders linked to obesity. J Am Soc Nephrol 15: 2792–2800.
Zhang XY, Zhou DF, Cao LY, Wu GY, Shen YC (2005). Cortisol and cytokines in chronic and treatment-resistant patients with schizophrenia: association with psychopathology and response to antipsychotics. Neuropsychopharmacology 30: 1532–1538.
Acknowledgements
This study was supported by funding through the National Alliance for Research on Schizophrenia and Depression, the National Institutes of Mental Health (R29-MH049746), and the Polier Endowed Chair in Schizophrenia and Related Disorders at Cedars-Sinai Medical Center.
Author information
Authors and Affiliations
Corresponding author
Additional information
DISCLOSURE
Dr Rapaport is a consultant to and has received honoraria for presentations from Cyberonics, Forrest Labs, Roche, Pfizer, Sanofi Synthelabo, Solvay, Sumitomo, Wyeth, GlaxoSmithKline, Janssen Pharmaceutica, Neurocrine Biosciences, Eli Lilly, and Novartis; has received research support from Astra Zeneca, Pfizer, Janssen Pharmaceutica, GlaxoSmithKine, Forrest Labs, Eli Lilly, Abbott Laboratories, Corcept Therapeutics, Cyberonics, Novartis, Pharmacia Upjohn, Sanofi Synthelabo, Solvay, Wyeth, and UCB Pharma; and is a stockholder in Forrest Labs. Ms Bresee has no biomedical financial interests or potential conflicts of interest.
Rights and permissions
About this article
Cite this article
Rapaport, M., Bresee, C. Serial Mitogen-Stimulated Cytokine Production from Continuously Ill Patients with Schizophrenia. Neuropsychopharmacol 35, 428–434 (2010). https://doi.org/10.1038/npp.2009.145
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2009.145
