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While in vitro studies have demonstrated that a glucocorticoid receptor (GR) splice isoform, β-isoform of human GR (hGRβ), acts as a dominant-negative inhibitor of the classic hGRα and confers glucocorticoid resistance, the in vivo function of hGRβ is poorly understood. To this end, we created an adeno-associated virus (AAV) to express hGRβ in the mouse liver under the control of the hepatocyte-specific promoter. Genome-wide expression analysis of mouse livers showed that hGRβ significantly increased the expression of numerous genes, many of which are involved in endocrine system disorders and the inflammatory response. Physiologically, hGRβ antagonized GRα's function and attenuated hepatic gluconeogenesis through downregulation of phosphoenolpyruvate carboxykinase (PEPCK) in wild-type (WT) mouse liver. Interestingly, however, hGRβ did not repress PEPCK in GR liver knockout (GRLKO) mice. In contrast, hGRβ regulates the expression of STAT1 in the livers of both WT and GRLKO mice. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays demonstrated that hGRβ binds to the intergenic glucocorticoid response element (GRE) of the STAT1 gene. Furthermore, treatment with RU486 inhibited the upregulation of STAT1 mediated by hGRβ. Finally, our array data demonstrate that hGRβ regulates unique components of liver gene expression in vivo by both GRα-dependent and GRα-independent mechanisms., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Glucocorticoids are essential steroid hormones secreted from the adrenal gland in response to stress. Since their discovery in the 1940s, glucocorticoids have been widely prescribed to treat inflammatory disorders and hematological cancers. In the traditional view, glucocorticoids are regarded as anti-inflammatory molecules; however, emerging evidence suggests that glucocorticoid actions are more complex than previously anticipated. The anti-inflammatory activity of glucocorticoids is attributed to the repression of pro-inflammatory genes through signal transduction by their steroid receptor, the glucocorticoid receptor (GR). The mechanisms modulating the pro-inflammatory effects of glucocorticoids are not well understood. In this review, we discuss recent findings that provide insights into the mechanism by which GR signaling can play a dual role in the regulation of the immune response. We hypothesize that these apparently opposite processes are working together to prepare the immune system to respond to a stressor (pro-inflammatory effects) and subsequently restore homeostasis (anti-inflammatory effects). Finally, we propose that determining the mechanisms which underlie the tissue-specific effects of glucocorticoids will provide an excellent tool to develop more efficient and selective glucocorticoid therapies., (© 2014 S. Karger AG, Basel.)

Severe inflammation leads to haemostatic abnormalities, such as the development of microvascular thrombi. As a result, ischaemia-related downstream organ damage can occur. The present study demonstrates that mice with a total deficiency of fibrinogen (Fg(-/-)) present with altered responses to challenge with Gram-negative lipopolysaccharide (LPS). Early survival in response to continuous LPS challenge was increased in Fg(-/-) mice and histological findings indicated that this improvement correlated with a lack of fibrin deposition in organs. Neutrophils appeared early in the lungs of challenged wild-type (WT) mice, but occurred in Fg(-/-) mice at later times. This delayed response in Fg(-/-) mice was confirmed by studies that showed a strong dependence on Fg of binding of neutrophils to endothelial cells in the presence of LPS. While cytokines were also elevated in both WT and Fg(-/-) mice, their levels were generally lower at early times in this latter group. The time course of MIP-2 expression correlated with the occurrence of pulmonary leakage after LPS challenge, which was delayed in Fg(-/-) mice. These results suggest that fibrin(ogen) plays a role as an early mediator in the cross-talk between coagulation and inflammation., (Copyright 2006 Pathological Society of Great Britain and Ireland.)