Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder

Abstract

Neuroplasticity may have a core role in the pathophysiology of major depressive disorder (MDD), a concept supported by experimental studies that found that excessive cortisol secretion and/or excessive production of inflammatory cytokines impairs neuronal plasticity and neurogenesis in the hippocampus. The objective of this study was to examine how changes in the glucocorticoid and inflammatory systems may affect hippocampal volumes in MDD. A multimodal approach with structural neuroimaging of hippocampus and amygdala, measurement of peripheral inflammatory proteins interleukin (IL)-6 and C-reactive protein (CRP), glucocorticoid receptor (GR) mRNA expression, and expression of glucocorticoid-inducible genes (glucocorticoid-inducible genes Leucin Zipper (GILZ) and glucocorticoid-inducible kinase-1 (SGK-1)) was used in 40 patients with MDD and 43 healthy controls (HC). Patients with MDD showed smaller hippocampal volumes and increased inflammatory proteins IL-6 and CRP compared with HC. Childhood maltreatment was associated with increased CRP. Patients with MDD, who had less expression of the glucocorticoid-inducible genes GILZ or SGK-1 had smaller hippocampal volumes. Regression analysis showed a strong positive effect of GILZ and SGK-1 mRNA expression, and further inverse effects of IL-6 concentration, on hippocampal volumes. These findings suggest that childhood maltreatment, peripheral inflammatory and glucocorticoid markers and hippocampal volume are interrelated factors in the pathophysiology of MDD. Glucocorticoid-inducible genes GILZ and SGK-1 might be promising candidate markers for hippocampal volume changes relevant for diseases like MDD. Further studies need to explore the possible clinical usefulness of such a blood biomarker, for example, for diagnosis or prediction of therapy response.

Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

“…Indeed, compared with rodents, relatively few neurons are being added to the human brain (25), and human postmortem brain studies have delivered conflicting results with regards to changes in hippocampal cell proliferation in depression and upon antidepressant treatment (26)(27)(28). It is also important to mention that one previous report has examined SGK1 mRNA expression in depressed patients, and found no difference compared with controls (29); this may likely be due to the fact that in their study, 29 of the 40 patients were on antidepressants, and not drug-free as in our study.…”

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

“…Interleukin-6 (IL-6) is a pleiotropic pro-inflammatory cytokine, whose peripheral concentration was found to be inversely related to hippocampal volume in MDD (Frodl et al 2012). The pathogenetic role of IL-6 in depression involves the acute phase of response, disorders in zinc and the erythron, HPA axis activation, induction of the tryptophan catabolite pathway, oxidative stress, autoimmune processes and neuroprogression (Maes et al 2014).…”

Association of Depressive Symptoms with Hippocampal Volume in 1936 Adults

“…Inflammation is an emerging area of interest in depression research (Eyre and Baune, 2012). Elevated levels of inflammatory biomarkers are associated with smaller hippocampal volumes in patients with MDD (Frodl et al, 2012).…”