Elsevier

Schizophrenia Research

Volume 54, Issue 3, 1 April 2002, Pages 281-291
Schizophrenia Research

Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor

https://doi.org/10.1016/S0920-9964(00)00094-3Get rights and content

Abstract

There is now evidence that schizophrenia may be accompanied by an activation of the monocytic and T-helper-2 (Th-2) arms of cell-mediated immunity (CMI) and by various alterations in the Th-1 arm of CMI. There is also evidence that repeated administration of typical and atypical antipsychotics may result in negative immunomodulatory effects. This study was carried out to examine (1) the serum concentrations of interleukin-8 (IL-8), IL-10, the soluble CD8 (sCD8) and the leukemia inhibitory factor receptor (LIF-R) in nonresponders to treatment with typical neuroleptics as compared with normal volunteers and responders to treatment; and (2) the effects of atypical antipsychotics on the above immune variables. The latter were determined in 17 nonresponders to treatment with neuroleptics and in seven normal volunteers and 14 schizophrenic patients who had a good response to treatment with antipsychotic agents. The nonresponders had repeated measurements of the immune variables before, and 2 and 4 months after treatment with clozapine or risperidone. Serum IL-8 and IL-10 were significantly higher in schizophrenic patients than in normal controls. The serum concentrations of the sCD8 were significantly increased 2 months, but not 4 months, after starting treatment with atypical antipsychotics. Serum LIF-R concentrations were significantly increased 2 and 4 months after starting treatment with atypical antipsychotics. It is concluded that: (1) schizophrenia is characterized by an activation of both pro-inflammatory and anti-inflammatory aspects of cell-mediated immunity; (2) prolonged treatment with atypical antipsychotics may increase the anti-inflammatory capacity of the serum in schizophrenic patients by increasing serum LIF-R concentrations; and (3) short-term treatment with clozapine may induce signs of immune activation which disappear upon prolonged treatment.

Introduction

There is now some evidence that the acute episode of schizophrenia is characterized by immune alterations, suggesting changes in (1) the monocytic arm; (2) the T-helper-1 (Th-1) and (3) the Th-2-like arms of cell-mediated immunity (CMI); and (4) by changes in the inflammatory response system (IRS). CD4+ T (helper) cells can be categorized into subsets, which secrete different patterns of cytokines. Th-1-like (CD4+) T cells produce, for example, interferon-γ (IFNγ) and interleukin-2 (IL-2) and potentiate the inflammatory response, while Th-2-like (CD4+) T cells produce IL-4 and IL-5 and also IL-10 (Cavaillon, 1996). IL-10 is an anti-inflammatory cytokine which inhibits Th-1-like functions and the production of monocytic pro-inflammatory cytokines (Cavaillon, 1996). In the rodent, IL-10 is a Th-2-like cytokine. In humans, however, the expression of IL-10 is not confined to a particular T cell subset, but is produced by a variety of cells, including Th-0, Th-1, Th-2 lymphocytes, B lymphocytes, and monocytes (Cavaillon, 1996).

There are some indications that the monocytic arm of CMI may be activated in schizophrenia. The findings include increased numbers of peripheral blood monocytes (Wilke et al., 1996) and an increased production of monocytic products or cytokines, such as IL-1, IL-6, tumor necrosis factor (TNF)-α, and the IL-1 receptor antagonist (IL-1RA) (Akiyama, 1999, Frommberger et al., 1997, Ganguli et al., 1994, Lin et al., 1998, Maes et al., 1995, Maes et al., 1997a, Maes et al., 1996, Maes et al., 1994, Monteleone et al., 1997, Naudin et al., 1996, Sirota et al., 1995, van Kammen et al., 1999, Wilke et al., 1996). IL-1, IL-6 and TNFα are pro-inflammatory cytokines, which are mainly, but not solely, secreted by monocytes (Cavaillon, 1996). It should be stressed, however, that not all studies were able to detect alterations in the plasma concentrations of the IL-1RA, TNFα, and IL-6 (Baker et al., 1996, Haack et al., 1999). However, the number of carriers of the IL-1β (−511; allele 1), IL-1α (−889; allele 2), and IL-1RA (allele 1) haplotype is significantly higher in schizophrenic patients than in controls, suggesting that cytokine aberrations in schizophrenia are, at least partly, genetically determined (Katila et al., 1999).

Schizophrenia is accompanied by signs of suppression and activation of the Th-1-like arm of CMI. Indicators of suppression of Th-1 functions are, for example, decreased mitogen-induced lymphocyte proliferation (Chengappa et al., 1995), decreased numbers of total T and Th cells (Muller et al., 1993) and decreased in vitro production of Th-1-like cytokines, such as interleukin-2 (IL-2) and interferon-γ (IFNγ) (Arolt et al., 1997, Ganguli et al., 1992, Kim et al., 1998). Indicators of activation of Th-1-like functions are, amongst others, increased serum concentrations of the IL-2R (Akiyama, 1999, Ganguli and Rabin, 1989, Gaughran et al., 1998, Maes et al., 1995, Maes et al., 1994, Rapaport et al., 1989), increased concentrations of IL-2 in serum or cerebrospinal fluid (CSF) (Kim et al., 1998, Licinio et al., 1993) and an increased number of CD4+ T cells and an increased CD4+/CD8+ ratio (Sperner-Unterweger et al., 1999). Some of the contradictory findings may be explained by (1) increased serum sIL-2R levels, which may compete with IL-2 for binding to cellular IL-2Rs (Caruso et al., 1993); and (2) the exhaustion theory, i.e. the hyporesponsiveness of peripheral blood mononuclear cells (PBMC) and decreased in vitro production of Th-1-like cytokines, which are caused by an overproduction of cytokines, such as IL-2, which render the immune cells refractory to respond properly to antigenic stimulation. In this respect, Kim et al. (1998) found, in the same schizophrenic patients, a significant increase of IL-2 serum concentrations and a significant decrease of the stimulated in vitro production of IL-2.

There are a few studies which suggest that Th-2-like functions may be increased in schizophrenia. Mittleman et al. (1997) reported higher concentrations of IL-4 in the CSF in juvenile first-onset schizophrenia.

Signs of activation of the IRS in schizophrenia are increased plasma concentrations of acute phase proteins or reactants, such as haptoglobin, alpha-1-acid glycoprotein, and alpha-1-antitrypsin, fibrinogen (Fb), complement component 3 (C3C) and C4 and hemopexin (Hpx) (Maes et al., 1997b, Smidt et al., 1988). Ahokas (1986) found increased immunoglobulin G (IgG), IgM and C3C in serum or CSF of schizophrenic subjects. Others, however, were unable to detect significant alterations in serum IgG, IgM, IgA, IgE and C3 and C4 complement fraction concentrations in schizophrenic patients (Cazzullo et al., 1998a, Cazzullo et al., 1998b).

There is also some evidence that the alterations in CMI or the IRS are more pronounced in treatment-resistant schizophrenic patients. Thus, Lin et al. (1998) found that serum IL-6 was significantly higher in schizophrenic patients suffering from treatment-resistant schizophrenia than in normal volunteers, whereas no significant differences were detected in responders and normal controls. It should be underscored, however, that it remains unknown as to whether the changes in CMI and the IRS are related to the pathophysiology or etiology of that illness. The changes could be related to an autoimmune process (DeLisi et al., 1985, Kirch, 1993), a viral infection or viral reactivation (DeLisi and Crow, 1986), or it could be the consequence of an aspecific response unrelated to the pathophysiology of schizophrenia, for example, psychological stress which is known to induce the production of cytokines, including IL-6, TNFα and IL-10 (Maes et al., 1998a, Maes et al., 1998b).

There is now evidence that antipsychotic agents modulate the production of monocytic and Th-1 cytokines and IL-10 and the activity of the IRS.

Haloperidol, but not clozapine, normalizes the initially increased serum IL-6 concentrations in acute schizophrenic patients (Maes et al., 1995, Maes et al., 1997a, Maes et al., 1994). In vivo, repeated administration of atypical antipsychotics, i.e. clozapine or risperidone, significantly increases the plasma concentrations of IL-6 and TNFα (Maes et al., 1997a, Maes et al., 1994, Pollmacher et al., 1996). Short-term treatment with clozapine (median=12 days) increases the plasma concentrations of IL-6 (Maes et al., 1997a), whereas prolonged treatment with antipsychotic agents significantly decreases IL-6R concentrations (Maes et al., 1995, Muller et al., 1997). In vitro, clozapine and haloperidol significantly increase the production of IL-1RA, which may antagonize the activities of IL-1 (Song et al., 2000). Haloperidol significantly inhibits the stimulated production of IL-1β and TNFα in a dose-dependent manner (Moots et al., 1999).

In vivo, repeated administration of atypical antipsychotics, i.e. clozapine or risperidone, significantly increases the plasma concentrations of IL-2R, indicating T cell activation (Maes et al., 1997a, Maes et al., 1994, Muller et al., 1997, Pollmacher et al., 1996). In vitro, clozapine and haloperidol significantly suppress the production of IL-2 and IFNγ (Leykin et al., 1997). Song et al. (2000), however, found that clozapine significantly increases the stimulated production of IFNγ.

In mice, chlorpromazine (CPZ) upregulates the secretion of IL-10 (Mengozzi et al., 1994, Tarazona et al., 1995).

Treatment with antipsychotic agents may suppress IRS activation in schizophrenia, i.e. the initial signs of the acute phase response are normalized after treatment (Maes et al., 1997b). Repeated administration of clozapine to schizophrenic patients significantly increases the plasma concentrations of plasma sCD8 (Maes et al., 1997a), a T cell antigen secreted by activated T lymphocytes (Aurelius et al., 1994, Tomkinson et al., 1989, Wijngaard et al., 1994). Increased plasma sCD8 concentrations are observed in immune disorders, e.g., autoimmune disorders (Becker et al., 1992, Linker-Israeli et al., 1994, Lipnick et al., 1993, Motohashi, 1993, Sawada et al., 1993).

Thus, the picture emerging is that: (1) typical antipsychotic agents have immunosuppressive activities through stimulation of the production of the IL-1RA and IL-10 and suppression of the production of pro-inflammatory cytokines, such as IL-6 and IFNγ; (2) repeated administration of atypical antipsychotics has immunosuppressive effects through a stimulated production of the IL-1RA and IL-2R; and (3) short-term treatment with clozapine may induce the production of pro-inflammatory cytokines such as IL-6, IFNγ and TNFα, an effect that disappears upon prolonged treatment.

However, to the best of our knowledge no research has examined serum IL-8, the leukemia inhibitory factor receptor (LIF-R) and IL-10, and the effects of antipsychotics on these immune variables in (treatment-resistant) schizophrenic patients. IL-8 is produced by monocytes, macrophages, neutrophils and endothelial cells after stimulation by IL-1 and TNFα (Cavaillon, 1996). IL-8 induces the chemotaxic activity in neutrophils, lymphocytes, natural killer cells, eosinophils and basophils (Cavaillon, 1996). LIF is a pleiotropic cytokine, which shares many functional actions with IL-6, such as induction of the acute-phase response (Bock et al., 1992, Cavaillon, 1996). The serum concentrations of the LIF-R can block the activities of LIF (Layton et al., 1992). Based on previous research results, we expected to find (1) increased serum IL-8 and IL-10 but lower serum LIF-R in schizophrenia; and (2) that atypical antipsychotics suppress serum IL-8 and increase serum IL-10, sCD8 and LIF-R.

The specific aims of the present study were to examine whether (1) treatment-resistant schizophrenia is accompanied by immune changes, such as increased serum IL-8, IL-10 and sCD8 and lowered LIF-R concentrations; and (2) long-term treatment with the atypical antipsychotic agents, clozapine and risperidone, normalizes signs of immune activation in patients with treatment resistance to typical neuroleptics.

Section snippets

Subjects

The subjects were 31 patients with schizophrenia, i.e. 17 nonresponders to treatment and 14 responders, and seven normal controls. All patients were admitted to the Psychiatric Rehabilitation Center IRCCS S. Giovanni di Dio-Fatebenefratelli, Brescia, Italy. This was a planned study which aimed to examine: (1) the IRS in relation to treatment resistance in schizophrenic patients; and (2) the effects of atypical antipsychotics, i.e. clozapine or risperidone, on the IRS. Therefore, among the

Results

There were no significant differences (F=2.2, df=2/35, P=0.1) in age between normal volunteers (mean age=40.4±8.8 years), responders (mean=40.0±13.2 years) and nonresponders (mean age=48.6±13.0 years). There were no significant correlations between age and serum IL-8 (r=0.29, P=0.07), IL-10 (r=0.14, P=0.6), sCD8 (r=0.11, P=0.5), and LIF-R (r=0.24, P=0.14). There were no significant differences (χ2=0.4, df=2, P=0.8) in the male/female ratio between normal volunteers (4/3), responders (8/6) and

Discussion

The major findings of this study are that patients with schizophrenia exhibit significantly increased serum concentrations of IL-8 and IL-10 as compared with normal controls, and that treatment with atypical antipsychotics for 2 months increased the serum concentrations of sCD8 and the LIF-R. Increased concentrations of IL-8 in schizophrenic patients may be in accordance with previous findings that schizophrenia is accompanied by an activation of the monocyte–macrophage arm of CMI. Indeed, IL-8

Acknowledgments

The research reported was supported in part by the IRCCS, Fatebenefratelli, Brescia, Italy and the CRC-MH, Antwerp, Belgium; and the Staglin Investigator Award (NARSAD) to Dr M. Maes. The secretarial assistance of Mrs M. Maes is greatly appreciated.

References (66)

  • E.G Gutierrez et al.

    Blood-borne interleukin-1 receptor antagonist crosses the blood–brain barrier

    J. Neuroimmunol.

    (1994)
  • M Haack et al.

    Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis

    J. Psychiatr. Res.

    (1999)
  • H.S Kim et al.

    Cyclosporine A and prednisolone inhibit lectin- and alloantigen-induced release of sCD8: correlation with proliferative responses

    Clin. Immunol. Immunopathol.

    (1991)
  • Y.K Kim et al.

    Decreased interleukin-2 production in Korean schizophrenic patients

    Biol. Psychiatry

    (1998)
  • I Leykin et al.

    Short and long term immunosuppressive effects of clozapine and haloperidol

    Immunopharmacology

    (1997)
  • A Lin et al.

    The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6

    Schizophr. Res.

    (1998)
  • R.N Lipnick et al.

    Elevated soluble CD8 antigen and soluble interleukin-2 receptors in the sera of patients with juvenile rheumatoid arthritis

    Clin. Immunol. Immunopathol.

    (1993)
  • M Maes et al.

    Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with haloperidol

    Eur. Neuropsychopharmacol.

    (2000)
  • M Maes et al.

    Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers

    J. Psychiatr. Res.

    (1995)
  • M Maes et al.

    In vivo immunomodulatory effects of clozapine in schizophrenia

    Schizophr. Res.

    (1997)
  • M Maes et al.

    Lower plasma CC16, a natural anti-inflammatory protein and increased plasma interleukin-1-receptor-antagonist in schizophrenia

    Schizophr. Res.

    (1996)
  • M Maes et al.

    The acute phase protein response in schizophrenia, mania and major depression: effects of psychotropic drugs

    Psychiatry Res.

    (1997)
  • M Maes et al.

    The effects of psychological stress on humans: increased production of pro-inflammatory cytokines and a Th1-like response in stress-induced anxiety

    Cytokine

    (1998)
  • P Monteleone et al.

    Plasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: effects of clozapine treatment

    Psychiatry Res.

    (1997)
  • J Naudin et al.

    Elevated circulating levels of IL-6 in schizophrenia

    Schizophr. Res.

    (1996)
  • J.K Relton et al.

    Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat

    Brain Res. Bull.

    (1992)
  • P Sirota et al.

    Increased interleukin-1 and interleukin-3 like activity in schizophrenic patients

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1995)
  • C Song et al.

    In vitro immunosuppressive effects of clozapine and haloperidol: increased interleukin-1 receptor antagonist production

    Schizophr. Res.

    (2000)
  • B Sperner-Unterweger et al.

    T-cell subsets in schizophrenia: a comparison between drug-naive first episode patients and chronic schizophrenic patients

    Schizophr. Res.

    (1999)
  • E Suzuki et al.

    Induction of interleukin-1 beta and interleukin-1 receptor antagonist mRNA by chronic treatment with various psychotropics in widespread area of rat brain

    Neurosci. Lett.

    (1996)
  • D.P van Kammen et al.

    Elevated interleukin-6 in schizophrenia

    Psychiatry Res.

    (1999)
  • Y Watanabe et al.

    Extracellular presence of IL-8 in the astrocyte-rich cultured cerebellar granule cells under acidosis

    Life Sci.

    (1998)
  • A Ahokas

    Immunoglobulin and C3 abnormalities in acute psychiatric disorders

    Acta Psychiatr. Scand.

    (1986)
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