The Proceedings of the American Thoracic Society 2:313-319 (2005)
© 2005 The American Thoracic Society
Glucocorticoid Pathways in Chronic Obstructive Pulmonary Disease Therapy
Ian M. Adcock and
Kazuhiro Ito
Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom
Correspondence and requests for reprints should be addressed to Ian M. Adcock, Ph.D., Cell and Molecular Biology, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. E-mail: ian.adcock{at}imperial.ac.uk
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ABSTRACT
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Lung function measures in patients with chronic obstructive pulmonary disease remain insensitive to corticosteroid actions, in contrast to the clinical improvements observed in most patients with asthma. By uncovering the reason for this paradox, physicians should be able to implement treatment regimens that restore corticosteroid sensitivity. Corticosteroids exert their effects by binding to a cytoplasmic glucocorticoid receptor, which is subjected to post-translational modification by phosphorylation. Receptor phosphorylation may influence hormone binding and nuclear translocation, as well as alter other glucocorticoid receptor interactions, its protein half-life, and downregulation processes. This suggests that a "phosphorylation code" may exist for glucocorticoid receptor function. Oxidative stress due to cigarette smoke may also be a mechanism for the corticosteroid resistance observed in chronic obstructive pulmonary disease, as it enhances proinflammatory transcription. Reduced glucocorticoid nuclear translocation along with attenuated histone deacetylase activity may be partially responsible for this effect. Therapies targeting these aspects of the glucocorticoid receptor activation pathway may reverse steroid resistance in patients with chronic obstructive pulmonary disease.
Key Words: glucocorticoid receptor phosphorylation • inhaled corticosteroids • oxidative stress • steroid resistance
Chronic obstructive pulmonary disease (COPD) has become one of the commonest diseases worldwide and a major global healthcare problem. It is now recognized that COPD involves a chronic inflammatory process affecting peripheral airways and lung parenchyma (1–4). COPD is a major and increasing global health problem (5) and is predicted to become the third commonest cause of death worldwide by 2020 (6). In the United Kingdom, COPD now causes more than 30,000 deaths a year. Even more importantly, COPD is an increasing cause of chronic disability and is predicted to become the fifth most common cause of disability in the world by 2020 (6). The European Respiratory Society reported that clinically relevant COPD now affects 4 to 6% of adults in Europe (7), and it already accounts for more than 20 million lost working days annually in the United Kingdom, placing an enormous burden on society.
Existing therapies for COPD are grossly inadequate. None has been shown to slow the relentless progression of the disease and, in sharp contrast to asthma, COPD appears to be relatively resistant to the antiinflammatory actions of corticosteroids (8). This review aims to describe the inflammatory nature of COPD and to indicate particular aspects of glucocorticoid function that are modified by oxidative stress, resulting in an inability of glucocorticoids to suppress COPD inflammation
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A CHRONIC INFLAMMATORY DISEASE
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Although the diagnosis, assessment of severity, and monitoring of COPD still rely on lung function tests, there is increasing interest in characterizing the type and intensity of airway inflammation, and in investigating whether this information is useful for management of the disease. For example, patients with COPD with significant reversibility after a course of corticosteroids have the pathological characteristics of asthma (9).
Current COPD guidelines do not include the presence of lower airway inflammation in their definitions (10–13). However, it is increasingly recognized that COPD is a chronic inflammatory disease of the small airways, and that the inflammation is worse during exacerbations (14). The pathologic hallmarks of COPD are destruction of the lung parenchyma (pulmonary emphysema), inflammation of the small peripheral airways (respiratory bronchiolitis), and inflammation of the central airways (15). Pathology studies show that inflammation in COPD occurs in the central and peripheral airways (bronchioles) and lung parenchyma (15). Most patients with COPD have all three pathologic conditions (chronic obstructive bronchitis, emphysema, and mucus plugging), but the relative extent of emphysema and obstructive bronchitis within individual patients can vary widely (16). Importantly, the inflammation seen in COPD increases in intensity with increasing disease severity (1).
There is a marked increase in macrophages and neutrophils in bronchoalveolar lavage fluid (BALF) and induced sputum from patients with COPD (15). Alveolar macrophages play a key role in COPD. Numbers are increased by 25-fold in patients with COPD compared with normal smokers (17), they are localized to sites of alveolar destruction, and they have the capacity to release chemotactic factors that attract neutrophils and T lymphocytes, as well as proteases that destroy elastin in the lung parenchyma to produce emphysema (5).
Patients with COPD have infiltration of macrophages and T cells (with an increased ratio between CD8+ and CD4+ T cells) in the airway wall and an increased number of neutrophils within the airway mucosa and lung parenchyma (15). The bronchioles are obstructed by fibrosis and infiltrated with macrophages and T lymphocytes. In contrast to the situation with asthma, eosinophils are not prominent except in patients with concomitant asthma or in some patients during exacerbations (15).
In COPD there is a marked increase in local and systemic oxidative stress (18–20), particularly during exacerbations (21). Most striking are the increases in reactive oxygen and nitrogen species, such as 4-hydroxynonenal, nitrotyrosine, hydrogen peroxide, and 8-isoprostane, that have been reported in sputum, BALF, exhaled breath condensate, and urine (22–25). Oxidative stress is increased because of the high concentration of oxidants in cigarette smoke, the production of oxidants by activated inflammatory cells, and a reduction in endogenous antioxidant mechanisms.
The inflammation found in COPD appears to be an amplification of the normal inflammatory response to inhaled noxious agents (cigarette smoke or other irritants), with increased numbers of inflammatory cells, cytokines, and proteases (3). The molecular mechanisms for this exaggerated inflammatory response are not yet fully understood, but if identified they would help to explain why only a minority of smokers (about 20%) develop airflow limitation.
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RESPONSE TO CORTICOSTEROIDS
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Inhaled corticosteroids (ICSs) are commonly prescribed in high doses for COPD, and in some countries they are used as frequently by patients with COPD as by those with asthma, but evidence of a beneficial effect in patients solely with COPD is weak. Long-term clinical trials with high doses of ICSs in the treatment of stable COPD have been disappointing (7, 13, 26; reviewed in Barnes and Kleinert [5]), as they do not appear to arrest the progressive decline in lung function, even when treatment is started before the disease becomes symptomatic, and have a small and inconsistent effect on symptoms, quality of life, and severity of exacerbations. At the same time this treatment, particularly when prolonged for many years, can produce systemic adverse effects, including skin bruising, adrenal suppression, cataracts, and loss of bone density (13, 26, 27), although not all studies report a significant change in bone density (28). The Global Initiative for Chronic Obstructive Lung Disease guidelines (13) state that regular treatment with ICSs, alone or in combination with inhaled long-acting ß2-agonists, should be prescribed only to patients with severe COPD (FEV1 < 50% of predicted value and repeated exacerbations requiring treatment with antibiotics and/or oral corticosteroids).
Thus, responsiveness to ICSs may be dependent on the severity of COPD (26, 29). ICS treatment of patients with Stage 3 COPD results in improved exacerbation rates (29) and quality-adjusted life expectancy, seemingly without additional cost compared with other therapies (30). This raises questions concerning which aspect of COPD is being targeted, as inflammation does not appear to be affected (see below).
Although it is well known that corticosteroids are effective at suppressing airway inflammation in asthma, their effects on lower airway inflammation in COPD are still controversial. This lack of clear clinical response is consistent with the demonstration that inhaled or oral steroids fail to reduce inflammatory cell numbers, cytokines, chemokines, or proteases in induced sputum or airway biopsies of patients with COPD (31–34). Corticosteroid-sensitive inflammatory proteins, such as tumor necrosis factor-
and interleukin-8, are not suppressed by corticosteroids in COPD, implying an active resistance mechanism. This may also be seen at the level of single cells, as alveolar macrophages from patients with COPD have higher baseline secretion of tumor necrosis factor-, interleukin-8, and matrix metalloproteinase-9, and corticosteroids are ineffective at suppressing these inflammatory proteins compared with cells from normal smokers and nonsmokers (35–37). Even in normal smokers there is an increase in inflammatory mediator secretion and a reduced antiinflammatory effect of corticosteroids (38).
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MECHANISMS OF GLUCOCORTICOID RECEPTOR FUNCTION
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Classically, corticosteroids exert their effects by binding to a single 777-amino acid glucocorticoid receptor (GR) that is localized to the cytoplasm of target cells. GRs are expressed in almost all cell types and their density varies from 200 to 30,000 per cell (39), with an affinity for cortisol of about 30 nM, which falls within the normal range for plasma concentrations of free hormone. GR has several functional domains (Figure 1). The corticosteroid ligand-binding domain is at the carboxyl terminus of the molecule and is separated from the DNA-binding domain by a hinge region. There is an N-terminal trans-activation domain that is involved in activation of genes once binding to DNA has occurred. This region may also be involved in binding to other transcription factors. The inactive GR is part of a large protein complex (about 300 kD) that includes two subunits of the heat shock protein hsp90, which blocks the nuclear localization of GR and one molecule of the immunophilin p59 (39).
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Figure 1. Modular structure of the human glucocorticoid receptor (GR). The modular design of GR enables distinct regions of the protein to function in isolation as ligand-binding domains, dimerization domains, nuclear localization domains, and trans-activation and trans-repression (AP-1–interacting and NF- B–interacting) domains. AF-1/AF-2 = activating factor-1/activating factor-2; GRE = glucocorticoid response element; hsp = heat shock protein; NLS = nuclear localization signal. Numbers above domains represent amino acid residues.
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Corticosteroids are thought to diffuse freely from the circulation into cells across the cell membrane and to bind to cytoplasmic GRs (Figure 2). Once the corticosteroid binds to GR, hsp90 dissociates, allowing the nuclear localization of the activated GR–corticosteroid complex and its binding to DNA (39). GR combines with another GR to form a dimer at consensus DNA sites termed glucocorticoid response elements (GREs) in the regulating regions of corticosteroid-responsive genes. This interaction allows GR to associate with a complex of DNA/protein-modifying and remodeling proteins, including steroid receptor coactivator-1 (SRC-1) and cAMP response element–binding protein (CREB)-binding protein (CBP), which produces a DNA–protein structure that allows enhanced gene transcription (39). The particular ligand, the number of GREs, and the position of the GREs relative to the transcriptional start site may be important determinants of the magnitude of the transcriptional response to corticosteroids (39).
The GR complex can regulate gene products in at least four other ways. First, GR acting as a monomer can bind directly or indirectly with the transcription factors activating protein-1 (AP-1) and nuclear factor (NF)-B, which are upregulated during inflammation, thereby inhibiting the proinflammatory effects of a variety of cytokines (39). Second, the GR dimer can bind to a GRE that overlaps the DNA-binding site for a proinflammatory transcription factor or the start site of transcription, thus blocking gene expression (39). Third, the GR dimer can induce the expression of the NF-B inhibitor IB- in certain cell types (40). Last, corticosteroids can increase the levels of cell ribonucleases and mRNA-destabilizing proteins, thereby reducing the levels of mRNA (41) (Figure 3). It is likely that the altered transcription of many different genes is involved in the antiinflammatory action of corticosteroids, but the most important action of these drugs may be to inhibit transcription of cytokine and chemokine genes implicated in inflammation (39).
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Figure 3. Changes in histone deacetylase-2 (HDAC2) activity and expression regulate inflammatory gene expression and corticosteroid function. Phosphorylation and nitration of specific tyrosine residues in HDAC2 induced by oxidative stress reduce HDAC2 activity. Nitration of HDAC2 leads to subsequent ubiquitination and proteasomal degradation. This results in enhanced inflammatory gene expression and a reduction in corticosteroid sensitivity. Reversal of these events by kinase inhibitors, phosphatases, or phosphorylation of distinct amino acids upregulates HDAC2 activity, thereby restoring corticosteroid actions and reducing the inflammatory response. PI3K/Akt = phosphoinositide 3-kinase/protein kinase B signaling pathway.
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Evidence of this has been described in a series of elegant experiments using mice expressing mutated GRs unable to dimerize and subsequently bind to DNA. In this model, Reichardt and colleagues (42, 43) have confirmed a role for GR DNA binding as a dimer in the control of proopiomelanocortin expression and T cell apoptosis, but not in that of inflammatory genes regulated by AP-1 or NF-B. This suggests that it will be possible to develop corticosteroids with a greater therapeutic window.
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NUCLEAR LOCALIZATION
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Control of nuclear protein import allows regulation of transcription factor activity and gene regulation (44, 45). Nuclear importation of proteins is an active process for proteins greater than 40 kD that contain a nonconsensus basic targeting sequence or nuclear localization sequence (NLS) (46). At least five NLS-binding or translocation proteins are known: importin- (karyopherin-), karyopherin-ß, hsp70, the small guanidine triphosphatase Ran, and p10 (nuclear transport factor-2). Importin binds specifically to the NLS, and this complex then binds to karyopherin-, which along with hsp70 mediates docking with the nuclear pore. Ran and its interacting protein p10 function in the active transport of the NLS-containing protein–importin complex through the nuclear pore, while importin- remains at the nuclear pore. Thus, the affinity of the NLS–importin- interaction is a critical parameter in determining nuclear transport efficiency.
The GR contains a classic basic NLS and a second, only poorly characterized NLS residing in the ligand-binding domain (47). Nuclear import via NLS1 proceeds more rapidly than that seen under NLS2 control (48). Studies have shown that nuclear import of GR is mediated through its NLS and interaction with importins, with importin- selectively binding to NLS1 (49) and importin-7 and importin-8 binding to both NLS1 and NLS2 (50). GR nuclear export is also tightly regulated; however, the role of the exportin-1 (CRM-1) pathway is currently unclear (51, 52). Importantly, the NLS–importin- interaction is often influenced directly by the phosphorylation status of the imported proteins (46).
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GENE INDUCTION BY GR
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GR, like other transcription factors, increases gene transcription through an action on chromatin remodeling and recruitment of RNA polymerase II to the site of local DNA unwinding. DNA is tightly compacted around a protein core. This chromatin structure is composed of nucleosomes, consisting of an octamer of two molecules each of core histone proteins (H2A, H2B, H3, and H4) surrounded by about 146 bp of DNA. Expression and repression of genes are associated with alterations in chromatin structure by enzymatic modification of core histones (53). Specific residues (lysines, arginines, and serines) within the N-terminal tails of core histones are capable of being post-translationally modified by acetylation, methylation, ubiquitination, or phosphorylation, all of which have been implicated in the regulation of gene expression (53). Acetylation of lysines leads to a loss of the electrostatic attraction between charged histones and DNA, allowing DNA unwinding and subsequent recruitment of further large transcriptional coactivator complexes and RNA polymerase II (53). Recruitment of other factors is often aided by the formation of bromodomains by the acetylated lysine residues (53). Transcriptional coactivators such as CBP have intrinsic histone acetyltransferase (HAT) activity (54). This activity is therefore recruited to the site of active gene transcription by the binding of transcription factors to DNA. Increased gene transcription is therefore associated with an increase in histone acetylation, whereas hypoacetylation induced by histone deacetylases is correlated with reduced transcription or gene silencing (53, 55).
GR interacts with CBP and other transcriptional coactivator proteins, including SRC-1 and glucocorticoid receptor–interacting protein-1, that enhance local HAT activity (56, 57). In addition, correct association of GR with DNA and other proteins determines the assembly of coactivator complexes on GR target promoters, resulting in differential acetylation of histones on distinct lysine residues (58).
One important question that arises concerns whether there is a specific order of recruitment of factors to the activated GR complex that enables gene transcription. It appears that nuclear hormone receptors do not in themselves recruit all the cofactors required at the target promoters (59), but steroid receptor coactivators, recruited by receptors, can in turn recruit other coactivators, which in turn recruit SWI/SNF (a large multisubunit protein complex) and mediator complexes that aid the formation of the transcription initiation complex. Thus, histone acetylation can enhance the recruitment of large multiprotein complexes in a coordinated manner through bromodomain interactions (59).
Histone H1 phosphorylation may also play a role in gene expression activated by GR (60). Only the phosphorylated form of histone H1 can be displaced from the mouse mammary tumor virus (MMTV) promoter by GR. Furthermore, long exposure to corticosteroids leads to H1 dephosphorylation. This may explain the previously puzzling "refractory" state of the MMTV promoter obtained on long exposure to corticosteroids.
However, the story may be more complex, because, in vitro, GR has a "hit-and-run" mechanism of action rather than a stable association with the GRE (61). GR resided on DNA for less than 10 s before being ejected and replaced by another GR. This ejection may allow binding of additional regulatory factors that enhance gene transcription, such as HAT-containing complexes, and may also play a role in feedback regulation. Interestingly, in the absence of adenosine triphosphate and chromatin-remodeling factors, GR stably interacts with the corticosteroid-responsive MMTV long terminal repeat promoter (62).
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GENE REPRESSION BY GR
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In spite of the ability of corticosteroids to induce gene transcription, the major antiinflammatory effects of corticosteroids are through repression of inflammatory and immune genes. The inhibitory effect of corticosteroids appears to be due largely to interaction between activated GR and transcription factors, such as NF-B and AP-1, that mediate the expression of inflammatory genes (63). Full inflammatory gene expression probably requires that a number of transcription factors act together in a coordinated manner, and repression of a single transcription factor may only partially modify the full response. Glucocorticoids may be able to reduce inflammatory gene expression by repressing downstream targets of transcription factor activation, irrespective of the precise activated transcription factors involved.
GR, acting as a monomer, binds only to specific coactivator complexes that are activated by proinflammatory transcription factors (Figure 2). It is possible that the required residency time of GR on the GRE may be a factor in distinguishing trans-activation from trans-repression. In this model, low concentrations of corticosteroids lead to fewer activated GRs having long enough residency on DNA to recruit coactivator complexes, so transcription does not occur. In contrast, this requirement for residency does not affect the association between p65, the major subunit of NF-B, and GR, which can therefore occur at lower concentrations.
The interaction between proinflammatory transcription factors and GR may result in differing effects on histone modifications, such as acetylation/deacetylation through GR binding to or recruiting receptor corepressors such as nuclear receptor corepressor or, interestingly, under some conditions coactivator glucocorticoid receptor–interacting protein-1 and histone deacetylases (HDACs) (57, 64); alterations in chromatin remodeling (64); and direct repression of NF-B–associated HAT activity (64).
In addition, corticosteroids may play a role in repressing the action of mitogen-activated protein kinases (MAPKs), such as the extracellular signal–regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) (65–68), all of which are activated in COPD (3). Caelles and colleagues (66) have demonstrated that corticosteroids inhibit the phosphorylation and activation of JNK, resulting in a failure to phosphorylate c-Jun and Elk-1, reduced c-fos transcription, and a marked reduction in AP-1 activity. More recently, it has been shown that dexamethasone can rapidly induce the dual-specificity MAPK phosphatase-1 (MKP-1) and thereby attenuate p38 MAPK activation (69–71). Rogatsky and colleagues have in turn shown reciprocal inhibition of rat GR reporter gene activity by JNKs by a direct phosphorylation of Ser-246, whereas ERK can inhibit GR action by an indirect effect, possibly through phosphorylation of a cofactor (72).
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ROLE OF GR PHOSPHORYLATION
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GR is a phosphoprotein containing numerous potential phosphorylation sites, including those for ERK, p38 MAPK, protein kinase C, and protein kinase A. After DNA binding, GR interacts with a number of cofactors and the basal transcription complex to regulate GR-responsive genes, many of which are also phosphorylated. The role of receptor phosphorylation in receptor function is controversial, however, because promoter complexity and context may affect the ability of phospho-GR to regulate transcription. Evidence clearly suggests that altered GR phosphorylation status can affect GR–ligand binding (73), hsp90 interactions (74), subcellular localization (75, 76), nuclear–cytoplasmic shuttling (77, 78), and trans-activation potential (75), possibly through association with coactivator molecules (76).
Ligand binding induces GR hyperphosphorylation at seven sites, which regulates trans-activation and reduces nonspecific DNA binding (79), although this response varies during the cell cycle, with cells being less sensitive to corticosteroids during the G2/M phase (80). Thus, global changes in GR charge may affect its function as well as specific phosphorylation events. MAPK activation or overexpression can also target specific serine/threonine residues in GR, decreasing GR-mediated trans-activation (72, 81). In addition, evidence suggests that GR phosphorylation is involved in receptor turnover and that phosphorylation can target the receptor for hormone-mediated degradation (82). As such, phosphorylation-induced targeting of GR for ubiquitination and proteasomal degradation may play an important role in overall GR responsiveness.
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EFFECTS OF OXIDATIVE STRESS ON GR FUNCTION
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The relative lack of response to corticosteroids in COPD has also been linked to oxidative stress. Cigarette smoking is the primary cause of COPD, and the smoke contains more than 1018 oxidant molecules per puff (23, 83). This suggests that oxidative stress may be an important factor in inducing corticosteroid resistance in COPD. The resistance may be due to cigarette smoking itself, because corticosteroids are much less effective in reducing inflammatory cells in BALF and sputum from smoking patients with asthma compared with nonsmoking patients (84, 85). The resistance to corticosteroid action is maintained even in subjects who are no longer smoking. This implies that either the oxidant stress is persistent or that the initial chronic insult permanently alters the expression of a component involved in corticosteroid action. There is good evidence for prolonged persistence of oxidative stress involving long-acting lipid peroxidation products, such as 4-hydroxynonenal and isoprostanes, and a reduction in the antioxidant protein 
-glutamylcysteine synthetase (23, 83).
Okamoto and colleagues (86) have suggested that oxidative stress may influence corticosteroid function by inhibiting GR nuclear translocation. Indeed, we have reported that many patients with severe corticosteroid-insensitive asthma have a defect in GR nuclear translocation (87). Of interest is the fact that respiratory viruses are important exacerbation triggers (88), and evidence has suggested that rhinoviral infection can reduce GR nuclear translocation and corticosteroid function (89).
Other potential causes of reduced corticosteroid function involve nuclear events. Histone deacetylases are important for corticosteroid-mediated suppression of NF-B activity, and the expression and activity of HDAC2 is decreased in BALF macrophages and biopsy specimens from smokers and patients with COPD (8, 90). This decrease correlates with increased inflammatory gene expression and reduced responsiveness to corticosteroids and cigarette smoke extract (91), and it can be mimicked by pretreatment of macrophages with hydrogen peroxide (91). The reduction in HDAC2 activity and expression by oxidative stress may relate to nitration or phosphorylation of tyrosine residues within the active site of HDAC2, possibly leading to an initial loss of activity before HDAC2 degradation in the proteasome (92). The results suggest that oxidative stress, by repression of HDAC activity, can enhance the inflammatory response and modulate corticosteroid function in BALF macrophages (Figure 3).
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CONCLUSIONS
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The identification of an active resistance mechanism in COPD suggests that steroid resistance is potentially reversible, which would have enormous implications for the future therapy of this poorly responsive disease. Because oxidative and nitrative stress may inactivate HDAC2 and interfere with the action of other HDACs, antioxidants such as N-acetylcysteine or inhibitors of inducible NO synthase (NO synthase-2) should reverse steroid resistance. In addition, agents that directly activate HDAC2 activity are likely to prove effective in restoring corticosteroid sensitivity in COPD.
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ACKNOWLEDGMENTS
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The literature in this area is extensive, and many important studies were omitted because of constraints on space, for which the authors apologize. The authors thank Drs. Borja Cosio and Gaetano Caramori for helpful discussions.
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FOOTNOTES
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Supported by the Clinical Research Committee (RBH), Asthma UK, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Mitubishi Pharma.
Conflict of Interest Statement: None of the authors have a financial relationship with a commercial entity that has an interest in the subject of this article.
(Received in original form April 12, 2005; accepted in final form May 15, 2005)
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ABSTRACT
A CHRONIC INFLAMMATORY DISEASE
