Expression of tumor necrosis factor-α and interferon-γ mRNA in blood cells correlates with depression scores during an acute attack in patients with multiple sclerosis

doi:10.1016/S0306-4530(01)00068-3

Psychoneuroendocrinology

Volume 27, Issue 6, August 2002, Pages 671-681

https://doi.org/10.1016/S0306-4530(01)00068-3 Get rights and content

Abstract

Depression is a common problem in multiple sclerosis (MS) and affects about 50% of MS patients. Since a dysregulation of cytokine levels has been implicated in the pathogenesis of MS and alterations in cytokine serum levels have been found in depressive illness, we examined the relationship between depressive symptoms, cytokine mRNA expression levels of Th1-type and Th2-type cytokines and neurological disability among early diagnosed MS patients in a prospective study. Sixteen patients with clinically or laboratory supported MS were assessed using the Beck Depression Inventory (BDI) and the Kurtzke Expanded Disability Status Scale (EDSS). Cytokine mRNA in whole blood was serially determined by a new quantitative polymerase chain reaction (PCR) method. BDI sum scores (2,9 fold) and the expression levels of tumor necrosis factor-α (TNF-α; 4 fold), interferon-γ (IFN-γ; 4,6 fold) and interleukin-10 (IL-10; 6,1 fold) mRNA were increased in MS patients during an acute attack compared to age and sex matched healthy controls. We detected a significant positive correlation between TNF-α (r=0.55) and interferon-γ (r=0.54) mRNA expression and the BDI sum scores during an acute attack in MS patients. At follow-up after 3–6 months, only TNF-α mRNA expression was correlated with BDI sum scores (r=0.62 resp. r=0.31). No correlation of the BDI sum scores with Th2-type cytokine mRNA expression for interleukin-4 (IL-4) and interleukin-10 (IL-10) or with the extent of neurological disability was observed. The possible contribution of Th1-type cytokines to the development of depression in MS is discussed.

Introduction

Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system affecting young adults. Several lines of evidence support a modulatory role of cytokines in the pathogenesis of MS although it is not completely clear how the pattern of cytokine expression relates to disease activity (Riekmann et al., 1995, Ensoli et al., 1999).

The prevalence of depressive illness in multiple sclerosis exceeds that of the general population, and may even exceed the prevalence observed in other chronic diseases (Devins and Seland, 1987, Minden and Schiffer, 1990). Point prevalence rates of depression in samples of MS patients ranged from 15% to 36%, and lifetime prevalence rates as high as 54% have been reported (Joffe et al., 1987, Minden et al., 1987, Sadovnik et al., 1996).

Explanations for observed depression in MS patients include a reaction to a stressful illness with potential impact on all aspects of daily living (e.g., family, employment, social, independent self-care and so on) and the relation of depression to progression of neurological disability (Surridge, 1969, McIvor et al., 1984). Other authors adressed a possible genetic link between depression and MS (Joffe et al., 1987, Minden et al., 1987). However, more recent work suggests that depression in MS patients may also be the result of specific CNS involvement as detected by location and magnitude of lesion load (Rabins et al., 1986, Campbell et al., 1992). Signs of an activation of the immune system were described in major depressive disorder. The findings included increased CD4+ cells, increased CD56+ natural killer cells, increased CD4+/CD8+ ratio and increased production of proinflammatory cytokines (Syvälathi et al., 1985, Müller et al., 1993, Seidel et al., 1996, Sluzewska et al., 1996, Frommberger et al., 1997, Maes et al., 1997, Connor and Leonard, 1998).

Therefore our study aimed at examining whether a dysregulation of cytokines may correlate with depressive symptoms in multiple sclerosis. The mRNA expression pattern of Th1-type (TNF-α and IFN-γ) and Th2-type (IL-4 and IL-10) cytokines were determined by using a sensitive quantitative polymerase chain reaction (PCR) method directly after admission, 3–6 months and 12 months after discharge. This method was proven to be highly sensitive, reproducible and easy to perform (Kruse et al., 1997). Sixteen MS patients were assessed by using the BDI and EDSS at the given intervals.

Section snippets

Subjects and sample collection

Sixteen patients with early laboratory supported MS of the relapsing–remitting type who fulfilled the criteria for the diagnosis of MS (Poser et al., 1983) were included in this study. After approval by informed written consent, all patients were examined first during an acute relapse. The patients were, on average, 30.1 years old (range from 21–44 years) and included 12 women and four men. The patients had little disability as defined by the expanded disability status scale (mean EDSS<2.5).

Results

Demographic information on the patient and the control sample is presented in Table 1.

Whole blood mRNA expression levels for the proinflammatory cytokines TNF-α and IFN-γ were significantly increased in MS patients during an acute attack compared to age and sex matched healthy controls (Fig. 1a and b). At follow up 3–6 months and 1 year after discharge, the mean TNF-α and IFN-γ mRNA expression slowly decreased to the range of healthy controls which was more pronounced for IFN-γ (Fig. 1a and b).

Discussion

We found significantly higher levels of TNF-α (×4) and IFN-γ (×4.6) mRNA and a concomittant upregulation of IL-10 (×6.1) mRNA in MS patients during an acute attack when compared to healthy controls. These results confirm previous studies in which an upregulation of IFN-γ and TNF-α in MS patients on the mRNA or the protein level has been reported (Chofflon et al., 1992, Riekmann et al., 1995, Philippe et al., 1996, Monteyne and Cindic, 1998, Vandevyver et al., 1998, Ensoli et al., 1999). Higher

Acknowledgements

This study was supported by grants from the Interdisziplinäres Zentrum für Klinische Forschung (IZKF, C3).

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