Elsevier

Life Sciences

Volume 72, Issue 14, 21 February 2003, Pages 1549-1561
Life Sciences

Minireview
Molecular mechanisms of corticosteroid actions in chronic inflammatory airway diseases

https://doi.org/10.1016/S0024-3205(02)02446-3Get rights and content

Abstract

Although corticosteroids have been used for a long time as a very effective therapy of airway inflammatory diseases such as asthma, only recently the molecular basis of their mechanism of action has begun to be elucidated. These hormones exert their biological and pharmacological actions by binding to cytoplasmic receptors that, upon activation, translocate to the nucleus where they interact with specific genomic sequences thus modulating gene expression. However, many glucocorticoid effects responsible for their anti-inflammatory and anti-asthmatic activity take place irrespectively of receptor binding to DNA. In particular, ligand-bound glucocorticoid receptors can repress several different pro-inflammatory genes by physically associating, via protein-protein interactions, with various transcription factors and with the macromolecular complexes implicated in regulation of chromatin structure and function. In this regard, an important role is played by the influences of corticosteroids on the intrinsic histone acetyltransferase and deacetylase functions of coactivators and corepressors, respectively. Furthermore, the signal transduction pathways mediated by mitogen-activated protein kinases are newly recognized, key targets of glucocorticoids. Indeed, these enzymatic cascades are crucially involved in the regulation of gene expression in that they are essential for the activity of a high number of transcription factors. Therefore, the recent advances made in such a rapidly growing research field are providing new insights into the mode of action of corticosteroids, thereby also unveiling novel promising therapeutic strategies directly targeted to the molecular events underlying the inflammatory, immune, and apoptotic processes implicated in the pathogenesis of asthma and other airway diseases.

Introduction

Inflammation plays a central role in the pathogenesis of some widespread respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD) [49], [51]. The cellular and molecular events underlying both these conditions are driven and perpetuated by multifunctional molecules including cytokines, chemokines, growth factors, lipid mediators and their respective receptors, that all lead to the recruitment of inflammatory cells as well as to the activation of structural cells (e.g., epithelial cells, endothelial cells, airway smooth muscle cells, fibroblasts). However, specific features distinguish asthma from COPD with regard to the characteristics of the key inflammatory changes. In particular, asthma is characterized by bronchial eosinophilic infiltration and airway remodeling, which are supposed to be orchestrated by a predominant CD4+/T helper 2 (Th2) response [44], whereas in COPD there is rather an infiltration of CD8+ T lymphocytes, macrophages, and neutrophils [38], [71]. Asthmatic and COPD patients also show important differences in their responses to anti-inflammatory drugs. Among the latter, corticosteroids represent the most potent anti-asthma treatment currently available [11], whereas they are less effective in COPD management [13].

Corticosteroids are able to interrupt many of the inflammatory pathways involved in the pathogenesis of asthma [81], including the complex cell to cell communications mediated by the so-called “cytokine network”. However, although these compounds have been used as anti-inflammatory agents for a long time, only during the past few years the molecular mechanisms underlying their biological and pharmacological effects have begun to be elucidated. Therefore, the recent significant advances made within this research field are contributing to identify a broad spectrum of molecular targets of glucocorticoids including genomic DNA, histone-modifying enzymes, transcription factors, and signalling cascades activated by a wide range of stimuli [2].

The aim of this minireview is to briefly outline the main functional features of glucocorticoid receptors and to discuss some new developments concerning the molecular events involved in glucocorticoid-dependent regulation of gene expression, with particular emphasis on modulation of airway inflammation; the basic mechanisms responsible for the corticosteroid-insensitivity detectable in COPD patients and in some asthmatics will also be delineated.

Section snippets

Glucocorticoid receptors

Glucocorticoids exert their actions by binding to a specific, intracellular glucocorticoid receptor (GR). Within the human genome, GR is encoded on the long arm of chromosome 5 (region 5q31–32) and belongs to the large superfamily of nuclear receptors, that also includes the receptors for mineralocorticoids, sexual and thyroid hormones, retinoic acid, and vitamin D. All these receptors share a modular structure consisting of a short and well-conserved central DNA binding domain, flanked by a

Stimulation of gene transcription

Glucocorticoids induce gene transcription by a genomic mechanism dependent on binding of activated GR to GRE (transactivation). In particular, corticosteroids would favour, at the level of gene promoters located in proximity to GRE, the recruitment of transcription factors and RNA polymerase II [79]. This process is largely due to chromatin-dependent mechanisms [15], in that activated GRs can reach their nucleotide consensus sequences even when DNA is densely packaged around histone proteins.

Inhibition of gene transcription

The very effective control of airway inflammation exerted by glucocorticoids in asthma is largely mediated by inhibition of the transcriptional activity of several different genes encoding pro-inflammatory proteins such as cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-11, IL-13, TNF-α, GM-CSF), chemokines (IL-8, RANTES, MIP-1α, MCP-1, MCP-3, MCP-4, eotaxin), adhesion molecules (ICAM-1, VCAM-1, E-selectin), and mediator-synthesizing enzymes (i-NOS, COX-2, cytoplasmic PLA2) [2], [81].

Post-transcriptional regulation

Glucocorticoids can also modulate gene expression at a post-transcriptional level by reducing the half-life of some mRNAs. Indeed, these hormones are able to activate mRNA-degrading ribonucleases that target AU (adenine-uracil)-rich sequences located within the 3′ untranslated region [59]. In this regard, it is noteworthy that several AU sequences have been identified near the 3′ end of the mRNAs coding for the growth factor GM-CSF (granulocyte-macrophage colony-stimulating factor) and for the

Asthma

Although glucocorticoids are the most effective drugs currently available for asthma treatment, a few asthmatic patients fail to respond well to these compounds, with a small percentage showing complete resistance [8]. This impaired glucocorticoid responsiveness may depend on several molecular mechanisms, including an increased synthesis and/or activation of pro-inflammatory transcription factors such as AP-1 and NF-κB, a reduced expression of GR, or an altered affinity of GRs for their ligands

Conclusions

The very effective therapeutic action of corticosteroids in asthma depends on the wide range of their cellular and molecular targets. In this regard, considerable advances have been made during the last few years about the knowledge of the transcriptional and post-transcriptional mechanisms responsible for the anti-inflammatory and immunomodulatory activities of such hormones. In particular, it has recently become clear the importance of glucocorticoid interactions with histone modifying

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