Inflammatory activation is associated with a reduced glucocorticoid receptor alpha/beta expression ratio in monocytes of inpatients with melancholic major depressive disorder

L A Carvalho,V Bergink,H A Drexhage,T K Birkenhager,L Sumaski,J Wijkhuijs,W J Hoogendijk

doi:10.1038/tp.2013.118

Abstract

In this study, we used new technology to investigate whether a coherent pattern of enhanced expression of inflammatory and other immune activation genes in circulating monocytes is found in patients with major depression. Since a high inflammatory state of monocytes might be related to glucocorticoid resistance, we also included the genes for the two isoforms of the glucocorticoid receptor. For this study, we aimed at finding a similar coherent pattern of inflammatory and immune activation genes in monocytes of patients with MDD and recruited 47 medication-free melancholic MDD inpatients and 42 healthy controls. A quantitative-polymerase chain reaction (Q-PCR) monocyte gene expression analysis was performed using a panel of inflammatory-related genes previously identified as abnormally regulated in mood disorder patients. Selected serum cytokines/chemokines were assessed using a cytometric bead array. Depressive symptoms were analysed using Hamilton depression scores (HAMD). Thirty-four of the 47 monocyte inflammatory-related genes were significantly upregulated and 2 were significantly downregulated as compared to controls, the latter including the gene for the active GRα in particular in those with a high HAMD score. The reduced GRα expression correlated strongly to the upregulation of the inflammatory genes in monocytes. Serum levels of IL6, IL8, CCL2 and VEGF were significantly increased in patients compared to controls. Our data show the deregulation of two interrelated homoeostatic systems, that is, the immune system and the glucocorticoid system, co-occurring in major depression.

Highlights

Major depressive disorder (MDD) is a biologically and genetically heterogeneous disorder
We have focused our investigations on cytokines and on important cellular producers of these cytokines, namely monocytes and macrophages. Supporting this approach, our group has identified a coherent pattern of enhanced expression of inflammatory and other immune activation genes in circulating monocytes of patients with mood disorders other than MDD, namely bipolar disorder and postpartum psychosis.[9,10,11]
P was tested by univariate analysis of covariance (ANCOVA) vs control subjects; age and gender are included in this model

Summary

INTRODUCTION

Major depressive disorder (MDD) is a biologically and genetically heterogeneous disorder. We have focused our investigations on cytokines and on important cellular producers of these cytokines, namely monocytes and macrophages Supporting this approach, our group has identified a coherent pattern of enhanced expression of inflammatory and other immune activation genes in circulating monocytes of patients with mood disorders other than MDD, namely bipolar disorder and postpartum psychosis.[9,10,11]. The use of one single cell type (i.e. monocytes instead of peripheral blood mononuclear cell) reduces the ranges of factors that may lead to inconsistency activation of the inflammatory system co-occurs with hyperactivity of the hypothalamic-pituitary-adrenal axis[18] and with impaired GR sensitivity[19] in treatment-resistant depressed patients. Expression values were calculated using the comparative threshold cycle method

Participants

RESULTS

DISCUSSION