Endothelial Response to Glucocorticoids in Inflammatory Diseases

Abstract

The endothelium plays a crucial role in inflammation. A balanced control of inflammation requires the action of glucocorticoids (GCs), steroidal hormones with potent cell-specific anti-inflammatory properties. Besides the classic anti-inflammatory effects of GCs on leukocytes, recent studies confirm that endothelial cells also represent an important target for GCs. GCs regulate different aspects of endothelial physiology including expression of adhesion molecules, production of pro-inflammatory cytokines and chemokines, and maintenance of endothelial barrier integrity. However, the regulation of endothelial GC sensitivity remains incompletely understood. In this review, we specifically examine the endothelial response to GCs in various inflammatory diseases ranging from multiple sclerosis, stroke, sepsis, and vasculitis to atherosclerosis. Shedding more light on the cross talk between GCs and endothelium will help to improve existing therapeutic strategies and develop new therapies better tailored to the needs of patients.

Keywords: adhesion molecules; cytokines; endothelium; glucocorticoid resistance; glucocorticoids; inflammation; tight junctions.

Figure 1

Splice variants and posttranslational modifications of the human glucocorticoid receptor (GR). (A) The splice variant GRβ differs from GRα in the C-terminal LBD, does not bind GCs, and acts as a dominant negative regulator of GRα. GRγ contains an insertion of an additional arginine residue in the DBD. This impairs its ability to regulate specific GC-responsive genes. GR-A and GR-P miss large regions in the LBD and fail to bind GCs, based on Oakley and Cidlowski (45). (B) GR contains several residues subjected to posttranslational modifications. AF, activation function; DBD, DNA-binding domain; HR, hinge region; LBD, ligand-binding domain; NLS, nuclear localization signal; NTD, N-terminal domain; P, phosphorylation; S, sumoylation; U, ubiquitination.

Figure 2

GCs exert specific actions in endothelial cells. In general, GCs have a variety of cell type-specific effects. This figure depicts GC actions that have been described in endothelium. After entering an endothelial cell, GCs bind to GC receptor (GR) and translocate to the nucleus. GR bound to GCs inhibits pro-inflammatory pathways by limiting GATA and AP-1 DNA binding and NF-κB translocation. GCs decrease levels of adhesion molecules (VCAM-1, ICAM-1, and E-selectin) and also their soluble forms and MMP-9 while increasing levels of junctional proteins—occludin, claudin-5, and VE-cadherin. GCs induce protective molecules such as AnxA1, TTP, MKP-1, and TIMPs. Furthermore, GCs reduce levels of IL-6, IL-17F, CXCL8 (IL-8), and CCL2 (MCP-1). Stimulation with GCs increases the activity of eNOS—a critical mediator of vascular integrity. Induction of ROS represents detrimental effects of GC excess on the vasculature.

Figure 3

Proteasomal degradation and epigenetic modifications regulate glucocorticoid sensitivity in endothelial cells. Proteasomal degradation of the glucocorticoid receptor (GR) impairs GR activity and prevents physiological actions of GCs. In dexamethasone-resistant HUVECs, GR associates with the proteasomal recruiting protein BCL2-associated athanogene 1 (BAG1). This results in a shorter half-life of GR. In HUVECs, low induction of SAP30 (component of Sin3A-histone deacetylase complex) impairs GR-mediated transrepression and leads to lower GC sensitivity. Furthermore, higher methylation of the promoters of the different variants of the untranslated exon 1 of GR leads to lower expression and therefore decreased GC sensitivity.

Figure 4

Endothelial GR signaling is beneficial in animal models of sepsis and atherosclerosis but harmful in stroke model. Mice with conditional GR deletion in endothelium provide a useful tool to study the role of endothelial GR signaling. In a model of stroke with these mice, it was shown that endothelial GR signaling increases infarct volume and reduces levels of junctional proteins (TJs) leading to increase in BBB permeability. In septic mice, the endothelial GR protects against LPS-induced inflammation and mortality. In an in vivo model of atherosclerosis, the endothelial GR reduces lesions and macrophage recruitment.