Elsevier

Biological Psychiatry

Volume 65, Issue 6, 15 March 2009, Pages 481-488
Biological Psychiatry

Archival Report
The Interaction of Nuclear Factor-Kappa B and Cytokines Is Associated with Schizophrenia

https://doi.org/10.1016/j.biopsych.2008.10.018Get rights and content

Background

Many reports suggest that schizophrenia is associated with the inflammatory response mediated by cytokines, and nuclear factor-kappa B (NF-κB) regulates the expression of cytokines. However, it remains unclear whether the interaction between NF-κB and cytokines is implicated in schizophrenia and whether the effect of neuroleptics treatment for 4 weeks is associated with the alteration of cytokines.

Methods

Sixty-five healthy subjects and 83 first-episode schizophrenic patients who met DSM-IV criteria and who were never treated with neuroleptics previously were included. Serum levels of cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were examined by using sandwich enzyme immunoassay (EIA). Peripheral blood mononuclear cell (PBMC) mRNA expressions of cytokines (IL-1β, TNF-α) and NF-κB were detected by using semiquantitative reverse transcription polymerase chain reaction (RT-PCR). NF-κB activation was examined by using transcription factor assay kits.

Results

Schizophrenic patients showed significantly higher serum levels and PBMC mRNA expressions of IL-1β and TNF-α compared with healthy subjects. However, treatment with the neuroleptic risperidone for 4 weeks significantly decreased serum levels and PBMC mRNA expressions of IL-1β in schizophrenic patients. NF-κB activation and PBMC mRNA expression in patients were significantly higher than those in healthy subjects. Furthermore, PBMC mRNA expressions of IL-1β and TNF-α were positively correlated to NF-κB activation in both schizophrenic patients and healthy control subjects.

Conclusions

Schizophrenic patients showed activation of the cytokine system and immune disturbance. NF-κB activation may play a pivotal role in schizophrenia through interaction with cytokines.

Section snippets

Participants

All the subjects gave written informed consent to participate in the study, which was approved by the Ethics Committee of Henan Mental Hospital. One hundred forty-eight subjects were invited to participate in the study, including 65 healthy control subjects (35 men and 30 women) and 83 patients (43 men and 40 women). Eligible patients were diagnosed according to DSM-IV criteria (27) with first-episode schizophrenia. The diagnosis of schizophrenia was determined by a psychiatrist using the

Demographic Data

Demographic data from 148 examined subjects are listed in Table 1. Because of matching criteria, there was no difference in age, sex, smoking, and BMI between the schizophrenic patients and healthy subjects.

Differences in Control Subjects and Schizophrenic Patients at Baseline

Serum levels and PBMC mRNA expressions of IL-1β and TNF-α in the schizophrenia group were significantly higher than those in control subjects. NF-κB activation and mRNA expression in the schizophrenia group were significantly higher than those in control group (Table 2, Figure 1).

Changes in Serum Levels and PBMC mRNA Expression of IL-1β and TNF-α After 4 Weeks of Risperidone Treatment

Serum

Discussion

In this study, we found a significant increase in serum levels of IL-1β and TNF-α in schizophrenic patients. This is consistent with previous reports that IL-1 and TNF-α are increased in plasma and cerebrospinal fluid of schizophrenic patients (31, 32, 33, 34, 35). The alterations of cytokines in schizophrenia have been extensively studied (36, 37, 38, 39). Many reports have demonstrated that IL-2 receptors express on pyramidal cells of brain regions including the hippocampus, and IL-2 may

References (65)

  • M. Maes et al.

    Effects of atypical antipsychotics on the inflammatory response system in schizophrenia patients resistant to treatment with typical neuroleptics

    Eur Neuropsychopharmacol

    (2000)
  • J. Naudin et al.

    A differential role for interleukin-6 and tumor necrosis factor-alpha in schizophrenia?

    Schizophr Res

    (1997)
  • A. Lin et al.

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

    Schizophr Res

    (1998)
  • S. Potvin et al.

    Inflammatory cytokine alterations in schizophrenia: A systematic quantitative review

    Biol Psychiatry

    (2008)
  • F. Gaughran

    Immunity and schizophrenia: Autoimmunity, cytokines, and immune responses

    Int Rev Neurobiol

    (2002)
  • M. Rothermundt et al.

    Review of immunological and immunopathological findings in schizophrenia

    Brain Behav Immun

    (2001)
  • S.S. Zalcman

    Interleukin-2-induced increases in climbing behavior: Inhibition by dopamine D-1 and D-2 receptor antagonists

    Brain Res

    (2002)
  • J. Kowalski et al.

    Neuroleptics normalize increased release of interleukin-1 beta and tumor necrosis factor-alpha from monocytes in schizophrenia

    Schizophr Res

    (2001)
  • A.H. van den Biggelaar et al.

    Inflammation and interleukin-1 signaling network contribute to depressive symptoms but not cognitive decline in old age

    Exp Gerontol

    (2007)
  • J.M. Cyranowski et al.

    Depressive symptoms and production of proinflammatory cytokines by peripheral blood mononuclear cells stimulated in vitro

    Brain Behav Immun.

    (2007)
  • M. Hashimoto et al.

    Action site of circulating interleukin-1 on the rabbit brain

    Brain Res

    (1991)
  • P. Sirota et al.

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

    Prog Neuropsychopharmacol Biol Psychiatry

    (1995)
  • H. Katila et al.

    Plasma levels of interleukin-1 beta and interleukin-6 in schizophrenia, other psychoses, and affective disorders

    Schizophr Res

    (1994)
  • T. Kato et al.

    Risperidone significantly inhibits interferon-gamma-induced microglial activation in vitro

    Schizophr Res

    (2007)
  • A. Larouche et al.

    Subacute H2O2, but not poly(IC), upregulates dopamine D2 receptors in retinoic acid differentiated SH-SY5Y neuroblastoma

    Synapse

    (2008)
  • N. Petrovsky

    Towards a unified model of neuroendocrine-immune interaction

    Immunol Cell Biol

    (2001)
  • M.G. De Simoni et al.

    Cytokine-neurotransmitter interactions in the brain

    Biol Signals Recept

    (1998)
  • N.J. Rothwell

    Cytokines—killers in the brain?

    J Physiol

    (1999)
  • M. Sawada et al.

    Induction of functional interleukin-2 receptor in mouse microglia

    J Neurochem

    (1995)
  • J.E. Merrill

    Tumor necrosis factor alpha, interleukin-1 and related cytokines in brain development: Normal and pathological

    Dev Neurosci

    (1992)
  • T.C. Pappas et al.

    Tumour necrosis factor-alpha- vs. growth factor deprivation-promoted cell death: Different receptor requirements for mediating nerve growth factor-promoted rescue

    Aging Cell

    (2003)
  • H. Neumann et al.

    Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism

    J Neurosci

    (2002)
  • Cited by (169)

    View all citing articles on Scopus

    XQS and LXL contributed equally to this article.

    View full text