Depressive symptomatology is associated with decreased interleukin-1 beta and increased interleukin-1 receptor antagonist levels in males

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Abstract

Previous studies with selected patient populations have suggested that cytokines, the immune system messengers, may play a role in the aetiology of depression. However, the data concerning the increase or decrease of the plasma cytokine levels in depression is controversial and the effects of the medications and type of depression are largely unknown. We studied the connections between plasma interleukin-1 beta (IL-1 beta) and interleukin 1 receptor antagonist (IL-1RA) levels, and depressive symptomatology measured with the Beck Depression. Inventory in a large, middle-aged population-based sample collected from Central Finland. In addition, the effects of various medications and type of depressive symptomatology on the cytokine levels were scrutinized. In the whole study population, IL-1RA levels were higher in the subgroup with depressive symptomatology. In the males with depressive symptomatology, higher IL-1RA levels and lower interleukin-1 beta levels were observed as compared with the non-depressed males. The IL-1RA/IL-1 beta ratio was significantly higher in males with depressive symptomatology. The IL-1RA levels were also higher and IL-1 beta levels lower in the depressed females, but the trend was not significant. The elevated IL-1RA-levels and IL-1RA/IL-1 beta ratio suggest a role for cytokines in the pathogenesis of depression. The higher IL-1RA levels may reflect an endogenous repairing process against depression.

Introduction

Depression is a prevalent and devastating psychiatric disorder with complex aetiology. In addition to disturbed monoaminergic neurotransmission, cytokines, the immune system messengers, have been suggested to be involved in the pathogenesis of depression (Owen et al., 2001, Rothermundt et al., 2001, Alesci et al., 2005, Dunn et al., 2005, Kaestner et al., 2005, Schiepers et al., 2005, Kim et al., 2007, Marques-Deak et al., 2007). For example, administration of the cytokine interferon-alpha for patients with hepatitis C and various forms of cancer has been shown to activate the cytokine system with increased levels of interleukin-2 receptor, interleukin-6 and interleukin-10. One third of these patients develop depression, anxiety, irritability, anorexia, and cognitive disturbances within 1 month after the administration of interferon-alpha (Beratis et al., 2005, Wichers et al., 2006). In a very recent longitudinal study of Wichers et al. (2007), serum cytokine levels were elevated and correlated positively with the Montgomery–Åsberg Depression Rating Scale scores during interferon-alpha treatment. Especially interleukin-2 receptor and interleukin-6 showed this positive correlation throughout the whole 24-week study period suggesting that treatment with interferon-alpha clearly increases the cytokine levels (Wichers et al., 2007).

In previous studies it has been demonstrated that pro-inflammatory cytokines may cross the blood–brain barrier and increase 5-HT turnover by activating the serotonin transporter (Leonard, 2001, Schiepers et al., 2005). They also affect 5-HT metabolism by stimulating the enzyme indoleamine 2,3-dioxygenase, which leads to peripheral depletion of tryptophan and reduced production of serotonin (Wichers and Maes, 2002). The pro-inflammatory cytokines (interleukins 1 and 6, tumour necrosis factor) may also induce hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis by reducing the function of the glucocorticoid receptor (Pariante and Miller, 2001). Thus the cytokines may induce malfunctioning of serotonergic neurotransmission and the HPA axis in the brain through mechanisms resembling those found in depression. Cytokines play also an important role in vascular diseases and metabolic disorders, such as insulin resistance (Charo and Taubman, 2004). A combined elevation of interleukin-1 beta and interleukin-6 has been reported to increase the risk of type 2 diabetes (Spranger et al., 2003, Charo and Ransohoff, 2006).

Within the immune system the activity of the pro-inflammatory cytokine interleukin-1 beta is antagonized by the IL-1 receptor antagonist (IL-1RA). The production ratio between IL-1RA and IL-1 beta has been shown to predict the clinical outcome and therapy response in various inflammatory and immune disorders (Kaestner et al., 2005). Initially, a rise in pro-inflammatory cytokines, such as IL-1 beta, has been observed in depression (Owen et al., 2001, Kaestner et al., 2005). However, as subsequent results from various clinical samples concerning the connection between cytokine levels and depressive symptomatology have been inconsistent (Rothermundt et al., 2001, Schiepers et al., 2005, Marques-Deak et al., 2007), we decided to study the association between plasma IL-1 beta and IL-1RA levels and the IL-1RA/IL-1 beta ratio with depressive symptomatology measured with the Beck Depression Inventory in a general population-based sample stratified with different age cohorts. The IL-1 beta was chosen as one of the most important pro-inflammatory cytokines, IL-1RA as an anti-inflammatory protein that specifically antagonizes the activities of IL-1 beta, and the IL-1RA/IL-1 beta ratio as indicator of immune activity (Kenis and Maes, 2002). In addition, the effects of various medications and types of depressive symptomatology on cytokine levels were scrutinized.

Section snippets

Subjects

The study was conducted in Pieksämäki area, South-Savo, Finland in order to determine the prevalence of metabolic syndrome and associated features. All inhabitants born in the years 1942, 1947, 1952, 1957 and 1962 in Pieksämäki (N = 1294) were invited for a comprehensive health check-up during 1998. The participation rate was 923/1294, i.e. 71.3% (Vanhala et al., 2002). The study was carried out in accordance with the latest version of the Declaration of Helsinki. All participants gave a written

Results

The mean age of the whole study group was 46 years (S.D. ± 6 years). The individuals with depressive symptomatology (N = 78) consisted 8.4% of the whole study sample, and they were more often females, smokers and older than the subgroup without depressive symptomatology (Table 1). The IL-1RA levels were higher in the group with depressive symptomatology. There were no significant differences in the IL-1 beta levels, alcohol consumption, amount of physical activity, BMI or prevalence of MetS between

Discussion

The novel finding of our study, including a large number of subjects from a population-based sampling, was that after adjusting for age, BMI, MetS, use of anti-diabetics, anti-hypertensives and statins, and current alcohol and tobacco use, the IL-1RA/IL-1 beta ratio was significantly higher in males with depressive symptomatology. Secondly, when subdivided according to sex, higher IL-1RA and lower IL-1 beta levels were observed in males with depressive symptomatology; in females, this trend was

Acknowledgements

This work was supported by grants from the Central Finland Hospital District (MV), Finnish Psychiatric Association (YO), South-Savo Cultural Foundation (YO), and grant number 113 760 from the Academy of Finland (HK).

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