Glucocorticoid receptors in human airways

Abstract

Inhaled and intranasal glucocorticoids are the most common and effective drugs for controlling symptoms and airway inflammation in respiratory diseases such as asthma, allergic rhinitis, and nasal polyposis. The last few years have seen a growing understanding of the mechanisms of glucocorticoid action and, in particular, the receptor that mediates glucocorticoid actions, the glucocorticoid receptor (GR). In this revision we present an update on the GR gene, the expression and regulation of its gene products, namely GRα and GRβ, as well as their alterations in pathological states. GRα is responsible for the induction and repression of target genes, it is expressed in virtually all human cells and tissues, and its expression is known to be downregulated by glucocorticoids. GRβ has been found to act as a dominant negative inhibitor of GRα‐mediated transactivation in in vitro studies with transfected cells, but it does not appear to have a significant inhibitory effect on GRα‐mediated transrepression. In addition, for most tissues the expression of GRβ, at least at the mRNA level, is extremely low compared with that of GRα. Some pro‐inflammatory cytokines appear to upregulate the expression of GRβ, and increased GRβ expression has been reported in diseases associated with glucocorticoid resistance or insensitivity, such as bronchial asthma, nasal polyposis, and ulcerative colitis. However, the possible role of GRβ in modulating glucocorticoid sensitivity and/or resistance in vivo has been highly debated and it is not yet clear.

Nuclear bioavailability of the glucocorticoid receptor in a pediatric asthma cohort with variable corticosteroid responsiveness

“…Consistent with previous reports, corticosteroid treatment led to decreased expression of GR, which occurred earlier and was more pronounced at the protein than at the mRNA level (9). This is not surprising, since homologous downregulation of the receptor involves direct destabilization of the existing protein while decreased levels of GR mRNA are believed to be mainly a result of reduced transcription (9,20). We show that GR expression decreased more rapidly in cells derived from PSR asthmatics at both the protein and mRNA levels, suggesting that the negative feedback mechanism in PSR children has a lower GC threshold for activation.…”

“…We previously identified importin 13 (IPO13), a nuclear import receptor for GR in the lung (8). Additionally, since corticosteroids induce GR downregulation, it is reasonable to speculate that differences in temporal activation of this negative feedback mechanism could also add to variations in corticosteroid sensitivity (9).…”

Mecanismos de ação dos corticosteróides na polipose rinossinusal

“…GRβ has the same GRE-binding capability, but does not bind to GC; GRβ, then, is considered an endogenous inhibitor of GC. Pujols et al 13 and Hamilos et al 15 reported increased GRβ expression in NSP patients, compared with controls. Valera 10 and Li et al 22 observed lower GRα levels in NSP, compared to the normal mucosa.…”

“…Valera 10 and Li et al 22 observed lower GRα levels in NSP, compared to the normal mucosa. Both Pujols et al 13 and Valera 10 stated that the most important factor in resistance to GC was the GRα/GRβ isoform ratio, more important then the absolute values of each isoform.…”

“…When bonding with these factors, the GC-GR complex blocks the transcription of cytokines, chemokines and enzymes such as IL-18, IL-16 and eotaxin, being thus directly related to their expresion. 13 Transcription factors are cytoplasmatic molecules that upon activation are able to translocate to the nucleus and to induce transcription of pro-inflammatory cytokines, adhesion molecules and chemokines, among others. GC, therefore, also suppress the transcription of pro-inflammatory cytokines (IL-1, IL-2, IL-3, IL-4, IL-, IL-6, GM-CSF, TNF-α, and IFN-γ), of chemokines (RANTES, eotaxin and MCP) and adhesion molecules (ICAM-1 and E-selectin).…”