MinireviewMolecular mechanisms of corticosteroid actions in chronic inflammatory 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
References (86)
Histone deacetylases: transcriptional repression with SINers and NuRDs
Trends in Cell Biology
(1999)- et al.
Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor-κB
Blood
(2001) - et al.
NF-κB: a pivotal role in asthma and a new target for therapy
Trends in Pharmacological Sciences
(1997) - et al.
Transcriptional regulation by steroid hormones
Steroids
(1996) - et al.
Heat shock protein interactions with the glucocorticoid receptor
Pulmonary Pharmacology and Therapeutics
(1998) - et al.
Lipocortin-1: cellular mechanisms and clinical relevance
Trends in Pharmacological Sciences
(1994) - et al.
Hormone-activated nuclear receptors inhibit the stimulation of the JNK and ERK signalling pathways in endothelial cells
FEBS Letters
(1999) - et al.
Signal transduction by the c-Jun N-terminal kinase (JNK): from inflammation to development
Current Opinion in Cell Biology
(1998) - et al.
p38 mitogen-activated protein kinase-induced glucocorticoid phosphorylation reduces its activity: role in steroid-insensitive asthma
Journal of Allergy and Clinical Immunology
(2002) - et al.
Glucocorticoids inhibit IL-4 and mitogen-induced IL-4Rα chain expression by different post-transcriptional mechanisms
Journal of Allergy and Clinical Immunology
(1998)
Repression of cyclooxygenase-2 and prostaglandin E2 release by dexamethasone occurs by transcriptional and post-transcriptional mechanisms involving loss of polyadenylated mRNA
Journal of Biological Chemistry
Effects of glucocorticoids on activation of c-Jun N-terminal, extracellular signal-regulated, and p38 MAP kinases in human pulmonary endothelial cells
Biochemical Pharmacology
Oxidative stress, transcription factors and chromatin remodeling in lung inflammation
Biochemical Pharmacology
In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosphorylation of Jun N-terminal kinase and failure of prednisolone to inhibit Jun N-terminal kinase phosphorylation
Journal of Allergy and Clinical Immunology
T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma
Journal of Allergy and Clinical Immunology
Review of the molecular and cellular mechanisms of action of glucocorticoids for use in asthma
Pulmonary Pharmacology and Therapeutics
Mechanisms of glucocorticoid-receptor-mediated repression of gene expression
Trends in Endocrinology and Metabolism
Steroid resistance in asthma: molecular mechanisms
American Journal of Respiratory and Critical Care Medicine
Molecular mechanisms of corticosteroid actions
Monaldi Archives for Chest Disease
Negative regulation by glucocorticoids through interference with a cAMP responsive enhancer
Science
Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids
Endocrine Reviews
Beta-adrenergic receptors and their regulation
American Journal of Respiratory and Critical Care Medicine
Glucocorticoid resistance in asthma
American Journal of Respiratory and Critical Care Medicine
Transcription factors and asthma
European Respiratory Journal
Efficacy and safety of inhaled corticosteroids: new developments
American Journal of Respiratory and Critical Care Medicine
Therapeutic strategies for allergic diseases
Nature
Chronic obstructive pulmonary disease
New England Journal of Medicine
Cytokine modulators as novel therapies for asthma
Annual Review of Pharmacology and Toxicology
Transcriptional control by nuclear receptors
FASEB Journal
Post-transcriptional regulation of granulocyte-macrophage colony-stimulating factor synthesis in murine T cells
Journal of Immunology
Detection of alveolar macrophage-derived IL-1β in asthma: inhibition with corticosteroids
Journal of Immunology
Nuclear hormone receptor antagonism with AP-1 by inhibition of the JNK pathway
Genes & Development
Elevated release of tumor necrosis factor-alpha and interferon-gamma by bronchoalveolar leukocytes from patients with bronchial asthma
American Review of Respiratory Disease
Mammalian MAP kinase signalling cascades
Nature
Glucocorticoids repress NF-κB-driven genes by disturbing the interaction of p65 with the basal transcription machinery, irrespective of coactivator levels in the cell
Proceedings of the National Academy of Sciences USA
MAP kinases in the immune response
Annual Review of Immunology
Glucocorticoids inhibit proliferation, cyclin D1 expression, and retinoblastoma protein phosphorylation, but not activity of the extracellular-regulated kinases in human cultured airway smooth muscle
American Journal of Respiratory Cell and Molecular Biology
Inhibition of Th1 immune response by glucocorticoids: dexamethasone selectively inhibits IL-12-induced Stat4 phosphorylation in T lymphocytes
Journal of Immunology
The coregulator exchange in transcriptional functions of nuclear receptors
Genes and Development
Control of transcription activation by steroid hormone receptors
FASEB Journal
Asthmatic epithelial cell proliferation and stimulation of collagen production
American Journal of Respiratory and Critical Care Medicine
Bronchial epithelium as a key regulator of airway allergen sensitization and remodeling in asthma
American Journal of Respiratory and Critical Care Medicine
Invited lecture: activation of the epithelial mesenchymal trophic unit in the pathogenesis of asthma
International Archives of Allergy and Immunology
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