Abstract
To examine immune-inflammatory and oxidative (I&O) biomarkers in major depression (MDD) and its related phenotypes, we recruited 114 well-phenotyped depressed patients and 50 healthy controls and measured serum levels of interleukin (IL)-1α, soluble IL-1 receptor antagonist (sIL-1RA), soluble IL-2 receptor (sIL-2R), soluble IL-6 receptor (sIL-6R), soluble tumor necrosis factor receptor 60 and 80 kDa (sTNF-R1/R2), and thiobarbituric acid reactive substances (TBARS). Obtained results indicate that MDD is characterized by increased sIL-1RA, sTNF-R1, and TBARS concentrations. Melancholic depression is associated with increased sIL-6R but lowered IL-1α levels. A current episode of depression is accompanied by significantly increased sIL-6R compared to the remitted state. Treatment-resistant depression (TRD) is accompanied by increased sIL-6R and TBARS but lowered sTNF-R2 levels compared to non-TRD patients. These immune markers are not significantly correlated with Hamilton Depression Rating Scale (HDRS), Montgomery-Asberg Depression Scale (MADRS), number episodes, or age at onset. Our findings show that increased sIL-1RA, sTNF-R1, and TBARS levels may be trait markers of depression, while increased sIL-6R levels may be a state marker of melancholia and an acute phase of depression. MDD is accompanied by increased lipid peroxidation and simultaneous activation of immune pathways, and the compensatory anti-inflammatory reflex system (CIRS). TRD is characterized by highly increased oxidative stress and probably increased TNFα and IL-6 trans-signalling. Novel treatments for major depression should target oxidative stress pathways, while new treatments for TRD should primary target lipid peroxidation and also activated immune-inflammatory pathways.
Highlights
Already in the 1990s, it was shown that major depression (MDD) is accompanied by an immune response and Thelper (Th)1 activation as indicated by elevated serum levels of soluble interleukin (IL)-2 receptor, increased expression of activation markers on peripheral blood mononuclear cells (PBMCs), e.g., Human Leukocyte Antigen-antigen D Related (HLA-DR) and cluster of differentiation 25 (CD25), resistance of cytokine production by immune cells to dexamethasone administration, and increased stimulated production of interferon (IFN)γ (Maes et al 1990, 1991, 1992a, 1994; Seidel et al 1995)
It was shown that major depression is accompanied by a chronic low-grade inflammatory response as indicated by increased levels of macrophage M1-related pro-inflammatory cytokines, including IL-1β and tumor necrosis factor (TNF)α, the soluble IL-1 receptor antagonist, increased IL-6 trans-signaling, and increases in positive acute phase proteins, such as haptoglobin, and complement factors (Maes et al 1991, 1992b, 1994, 1995a, b; Słuzewska et al 1995; Frommberger et al 1997; Mikova et al 2001)
thiobarbituric acid reactive substances (TBARS) was significantly correlated with soluble IL-1 receptor antagonist (sIL-1RA) (r = 0.201, p = 0.012, n = 155) and soluble IL-6 receptor (sIL-6R) (r = 0.210, p = 0.010, n = 150), but not IL-1α (r = 0.144, p = 0.076, n = 153), soluble interleukin (IL)-2 receptor (sIL-2R) (r = −0.058, p = 0.470, n = 157), Table 3 Marginal means (SE) obtained by general linear model (GLM) analyses in the second multivariate GLM analyses with healthy controls (HC), Treatment-resistant depression (TRD), and non-TRD as groups
Summary
Already in the 1990s, it was shown that major depression (MDD) is accompanied by an immune response and Thelper (Th) activation as indicated by elevated serum levels of soluble interleukin (IL)-2 receptor (sIL-2R), increased expression of activation markers on peripheral blood mononuclear cells (PBMCs), e.g., Human Leukocyte Antigen-antigen D Related (HLA-DR) and cluster of differentiation 25 (CD25), resistance of cytokine production by immune cells to dexamethasone administration, and increased stimulated production of interferon (IFN)γ (Maes et al 1990, 1991, 1992a, 1994; Seidel et al 1995). Activation of immune-inflammatory pathways in major depression has been consolidated in meta-analysis studies indicating increased IL-6, TNFα, sIL-2R, IL-1β, sIL-1RA, and C-reactive protein (CRP) levels in major depression (Howren et al 2009; Dowlati et al 2010; Liu et al 2012; Hiles et al 2012; Valkanova et al 2013; Haapakoski et al 2015; Köhler et al 2017) These meta-analyses showed that Th2 and Tregulatory (Treg) cytokines (including IL-10, IL4, and IL-5) were not significantly altered in major depression indicating that major depression is characterized by M1 and Th1 activation. These TNFα receptor subtypes act as decoy receptors by binding sTNFα thereby attenuating TNFα signaling and inhibiting TNFα activities (Selinsky et al 1998; Su et al 1998)
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