Review
Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: A meta-analysis and meta-regression

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Abstract

Background

Many studies have explored the association between soluble interleukin-2 receptor (sIL-2R), cytokines and major depressive disorder (MDD). However, the results of these studies were not consistent. The aim of our study is to compare the levels of sIL-2R and cytokines in the blood between MDD patients and controls by a meta-analysis and to identify moderators accounting for potential heterogeneity in the levels of sIL-2R and cytokines in MDD patients versus controls by meta-regression analyses.

Methods

A comprehensive literature search was performed to identify studies comparing the levels of sIL-2R and cytokines between MDD patients and controls. We pooled the effect sizes for standardized mean differences (SMD) of the levels of sIL-2R and cytokines. We also performed meta-regression and sensitivity analyses to investigate the roles of age, gender, sample type, ethnic origin and selected studies' quality in explaining potential heterogeneity and differences in results respectively.

Results

Twenty-nine studies were selected for this analysis. The levels of sIL-2R, TNF-α and IL-6 in MDD patients were significantly higher than those of healthy controls (SMD = 0.555, p < 0.001, SMD = 0.567, p = 0.010; SMD = 0.680, p < 0.001). Mean age of all subjects was a significant moderator to explain the high heterogeneity of IL-6. Sensitivity analysis found that European but not non-European subjects have higher levels difference of sIL-2R, TNF-α and IL-1β between MDD patients and controls.

Limitation

The severity of MDD was not considered.

Conclusion

The blood levels of sIL-2R, TNF-α and IL-6 were significantly higher in MDD patients than controls. Age, samples source and ethnic origins may play a potential role in heterogeneity.

Introduction

The lifetime prevalence of major depressive disorder (MDD) ranges from 4.4% to 20% in the general population (Sartorius, 2001). Thus far, despite decades of study, the pathogenic mechanism of depression remains elusive. While current theory suggests that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis plays an indispensible role in the pathogenesis of endogenous depression (Pariante and Lightman, 2008), the impact of inflammation on the occurrence of depression was firstly recognized at the early 1990s (Maes et al., 1990–1991, Maes et al., 1991a, Maes et al., 1991b, Maes et al., 1992a, Maes et al., 1992b, Maes et al., 1993). It was demonstrated that the levels of several inflammatory biomarkers in the blood such as acute phase proteins (C-reactive protein and haptoglobin) (Howren et al., 2009, Maes et al., 1994a); prostaglandin E2 (PGE2) (Lieb et al., 1983); secretory interlukin-1 receptor antagonist (sIL-1RA) (Maes et al., 1997) and complement factors (Song et al., 1994) were elevated in patients with MDD. Furthermore, the cell-mediated immune (CMI) activation may play a role in the pathogenesis of MDD (Maes, 2011). The levels of several CMI activation biomarkers including neopterin (Maes et al., 1994b), soluble tumour necrosis factor receptor (sTNFR) (Diniz et al., 2010b), sIL-2R (Maes et al., 1995a, Maes et al., 1995b) were elevated in patients with MDD. CMI can be defined as an immune response with the characteristics of the activation of antigen-specific cytotoxic T-lymphocytes, natural killer cells, macrophages and the release of different cytokines in response to different antigens. It was demonstrated that cytokines such as IL-2 and interferon-gamma (IFN-γ) involved in the activation of CMI which need the existence of interleukin-2 receptor (IL-2R) (Maes, 2011). IL-2R is an important receptor involving in the activation of T cell-mediated immune, which was found to be elevated in patients with MDD (Maes et al., 1995a, Maes et al., 1995b, Maes et al., 1995c, Sluzewska et al., 1996).

As the inflammatory system was activated in MDD (Maes, 1999), cytokines may also play an important role in its pathogenesis. Cytokines are classified into pro-inflammatory cytokines, cell mediated and anti-inflammatory cytokines (see Table 1). Previous studies have demonstrated that the levels of pro-inflammatory cytokines such as IL-6 was higher in patients with MDD as compared with to the healthy controls (Maes et al., 1995a, Maes et al., 1995b, Maes et al., 1997, Sutcigil et al., 2007, Yang et al., 2007). Vice-versa, it was also found that the mean blood levels of TNF-α for healthy controls were lower than patients with MDD (Sutcigil et al., 2007, Yang et al., 2007). Furthermore, it was found the levels of IL-10 were elevated in patients with MDD in several studies (Hernandez et al., 2008, Simon et al., 2008). However, such significant elevation was not reported by other researchers (Dhabhar et al., 2009, Huang and Lee, 2007, O'Brien et al., 2007). IL-10 is a key identified anti-inflammatory cytokine which is closely related with the activation of compensatory anti-inflammatory response syndrome (CARS) (Adib-Conquy and Cavaillon, 2009). CARS is an adaptive response which is aimed to reverse inflammatory process (Adib-Conquy and Cavaillon, 2009) and its role in depression is unclear. IL-10 is not only an anti-inflammatory cytokine, but also a cytokine produced by T helper (Th) 2 cells. When naive helper T cells are activated, they can develop into three kinds of helper cells: Th1 cells, Th2 cells and Th3 cells. Th1 cells participate in the immune process against antigen outside the cells and involve in the activation of B cells, cytotoxic T cells and macrophages. In contrast, the Th2 cells participate in the immune process against antigens in the cells. For the Th3 cells, they mainly involved in mucosal immunity. IFN-γ and IL-2 ascribe to Th1 like cytokines while IL-4 and IL-10 belong to Th2 like cytokines; transforming growth factor β (TGF-β) is a Th3 like cytokines (Maes, 2011) (see Table 1).

The aim of this meta-analysis is to study the role of pro-inflammatory, anti-inflammatory and cell mediate cytokines in MDD. This meta-analysis includes 6 new studies (Basterzi et al., 2005, Diniz et al., 2010a, Diniz et al., 2010b, Eller et al., 2009, Motivala et al., 2005, Yoshimura et al., 2010) which were not included in two previous 2 meta-analyses (Dowlati et al., 2010, Howren et al., 2009). We mainly focused on MDD as one previous meta-analysis conducted by Dowlati et al. (2010) included a study with subjects suffering from both depression and substance misuse (Berk et al., 1997). Furthermore, we analyzed the levels of sIL-2R between patients with MDD and healthy controls which was not reported in the previous meta-analyses. Meta-regression and sensitivity analyses were also performed to address whether age, gender, sample type, origin of subjects and quality of selected studies play potential roles in explaining the potential heterogeneity and differences of the sIL-2R and cytokines levels between patients with MDD and healthy subjects.

Section snippets

Search strategy

We performed a comprehensive literature review (1960 to February 2011) through PubMed and EmBase by using the search key words “sIL-2R”, “tumour necrosis factor”, “interferon gamma”, “interleukin”, “cytokine”, “inflammatory”, “depression” and “depressive disorder”. Bibliographies of the retrieved trials and review articles were also scanned and searched manually for relevant papers.

Criteria for selecting articles included in this meta-analyses

Cross-sectional studies which compared the blood levels of sIL-2R and cytokines between patients with MDD and

Literature searching results

Four thousand four hundred sixty-nine abstracts were initially identified. One hundred forty-seven papers were left after excluded reviews (n = 686), animal studies (n = 1675) and unrelated topic (n = 1961). After we excluded non-English publication (n = 1), studies with comorbid diseases or concomitant medications (n = 100), studies without control groups (n = 4), studies not using Diagnostic and Statistical Manual of Mental Disorders (DSM) as diagnostic criteria (n = 4), studies only with stimulated

Discussion

It was demonstrated in our meta-analysis that patients with MDD had higher levels of blood sIL-2R, TNF-α and IL-6 when compared with healthy subjects but no difference was found in anti-inflammatory and cell-mediated cytokines between the two groups. Mean age was a significant moderator in explaining the heterogeneity of IL-6. The differences in sIL-2R, TNF-α and IL-1β between depressed patients and controls were significant in European patients but not in non-European patients. The differences

Role of the funding source

No funding support.

Conflict of interest

No conflict of interest.

References (71)

  • Y.P. Liu et al.

    Tumor necrosis factor-alpha and interleukin-18 modulate neuronal cell fate in embryonic neural progenitor culture

    Brain Res.

    (2005)
  • M. Maes

    Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (2011)
  • M. Maes et al.

    Antiphospholipid, antinuclear, Epstein–Barr and cytomegalovirus antibodies, and soluble interleukin-2 receptors in depressive patients

    J. Affect. Disord.

    (1991)
  • M. Maes et al.

    Higher alpha 1-antitrypsin, haptoglobin, ceruloplasmin and lower retinol binding protein plasma levels during depression: further evidence for the existence of an inflammatory response during that illness

    J. Affect. Disord.

    (1992)
  • M. Maes et al.

    Increased neopterin and interferon-gamma secretion and lower availability of l-tryptophan in major depression: further evidence for an immune response

    Psychiatry Res.

    (1994)
  • M. Maes et al.

    Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression

    J. Affect. Disord.

    (1995)
  • M. Maes et al.

    Plasma soluble interleukin-2-receptor in depression: relationships to plasma neopterin and serum IL-2 concentrations and HPA-axis activity

    Eur. Psychiatry

    (1995)
  • M. Maes et al.

    Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression

    Cytokine

    (1997)
  • O. Mikova et al.

    Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis

    Eur. Neuropsychopharmacol.

    (2001)
  • A.M. Myint et al.

    Th1, Th2, and Th3 cytokine alterations in major depression

    J. Affect. Disord.

    (2005)
  • S.M. O'Brien et al.

    Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy

    J. Psychiatr. Res.

    (2007)
  • C.M. Pariante et al.

    The HPA axis in major depression: classical theories and new developments

    Trends Neurosci.

    (2008)
  • L. Pavon et al.

    Th2 cytokine response in major depressive disorder patients before treatment

    J. Neuroimmunol.

    (2006)
  • J.L. Pike et al.

    Dissociation of inflammatory markers and natural killer cell activity in major depressive disorder

    Brain Behav. Immun.

    (2006)
  • B.B. Simen et al.

    TNFalpha signaling in depression and anxiety: behavioral consequences of individual receptor targeting

    Biol. Psychiatry

    (2006)
  • N.M. Simon et al.

    A detailed examination of cytokine abnormalities in major depressive disorder

    Eur. Neuropsychopharmacol.

    (2008)
  • A. Sluzewska et al.

    Indicators of immune activation in major depression

    Psychiatry Res.

    (1996)
  • C. Song et al.

    Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls

    J. Affect. Disord.

    (1994)
  • J. Wei et al.

    Increase of plasma IL-6 concentraion with age in healthy subjects

    Life Sci.

    (1992)
  • P.F. Zangerle 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)
  • M. Adib-Conquy et al.

    Compensatory anti-inflammatory response syndrome

    Thromb. Haemost.

    (2009)
  • W.A. Banks

    Blood-brain barrier transport of cytokines: a mechanism for neuropathology

    Curr. Pharm. Des.

    (2005)
  • A.D. Basterzi et al.

    IL-6 levels decrease with SSRI treatment in patients with major depression

    Hum. Psychopharmacol.

    (2005)
  • P.H. Black

    Immune system-central nervous system interactions: effect and immunomodulatory consequences of immune system mediators on the brain

    Antimicrob. Agents Chemother.

    (1994)
  • F. Brambilla et al.

    Blood levels of cytokines in elderly patients with major depressive disorder

    Acta Psychiatr. Scand.

    (1998)
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    Division of Rheumatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

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