Purpose: Individuals with mood disorders and schizophrenia (SCZ) exhibit altered function of the HPA axis in response to stress. The glucocorticoid receptor (GR) plays an important role in negative feedback regulation of the HPA-axis. There are two protein isoforms, GRα and GRβ, which have activating and blocking activity respectively. In line with aberrant expression of GR mRNA in the brains of depressed, SCZ and bipolar (BD) patients (1), lymphocytes of depressed, SCZ and BD patients showed reduced response to dexamethasone (2, 3). Furthermore, we previously detected a pro-inflammatory gene expression signature in monocytes of SCZ and BD patients. We hypothesized that the expression of GRα and GRβ might be altered in monocytes of SCZ and BD patients resulting in steroid resistance in the monocytes of these patients coupled to the pro-inflammatory monocyte state.
Research design and methods: GRα and GRβ expression was investigated in monocytes of 32/22 SCZ/BD patients and 34/22 age/gender-matched healthy controls (HC) using quantitative PCR (qPCR). In a next step the Spearman rank correlation was calculated to assess the correlation between GRα, GRβ and the other inflammatory genes. The GRβ/α ratio was calculated to assess a possible glucocorticoid resistance in the monocytes of these patients.
Results: Up-regulated expression of GRβ was detected in 69/45% of the SCZ/BD patients, respectively. Down-regulated expression of GRα was detected in 53/41% of the SCZ/BD patients, respectively. Therefore, the GRβ/α ratio calculation revealed an increased ratio in SCZ>BD>HC (Table 1). Evaluation of qPCR data further revealed that increased expression of GRβ positively correlated with the expression of the previously described pro-inflammatory genes up-regulated in monocytes of SCZ and BD patients. Expression of GRα negatively correlated to the expression of the pro-inflammatory monocyte genes in SCZ patients, but this correlation was lost in BD patients.
Conclusions and perspectives: Our results indicate that GRβ expression is significantly up-regulated in pro-inflammatory monocytes of SCZ patients whereas GRα is down-regulated. The same results were found in BD patients, though to a lesser extent. The correlation analysis suggests that up-regulated GRβ expression leads to glucocorticoid insensitivity and is closely linked to the pro-inflammatory expression pattern in monocytes of all investigated groups. The down-regulated GRα expression is closely linked to loss of glucocorticoid sensitivity, but only in the SCZ and HC groups, this process seems to be uncoupled in BD patients.
30 Apr - 04 May 2011
European Society of Endocrinology