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Molecular Mechanisms of Corticosteroid Resistance* FREE TO VIEW

Ian M. Adcock, PhD; Peter J. Barnes, MD, FCCP
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*From the Airways Disease Section, National Heart and Lung Institute, Imperial College, London, UK.

Correspondence to: Ian M. Adcock, PhD, Cell and Molecular Biology, Airways Disease Section, National Heart & Lung Institute, Imperial College London, Guy Scadding Building, Dovehouse St, London SW3 6LY, UK; e-mail: ian.adcock@imperial.ac.uk



Chest. 2008;134(2):394-401. doi:10.1378/chest.08-0440
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Most patients with asthma are successfully treated with conventional therapy. Nevertheless, there is a small proportion of asthmatic patients, including present cigarette smokers and former cigarette smokers, who fail to respond well to therapy with high-dose glucocorticoids (GCs) or with supplementary therapy. In addition, high doses of steroids have a minimal effect on the inexorable decline in lung function in COPD patients and only a small effect on reducing exacerbations. GC insensitivity, therefore, presents a profound management problem in these patients. GCs act by binding to a cytosolic GC receptor (GR), which is subsequently activated and is able to translocate to the nucleus. Once in the nucleus, the GR either binds to DNA and switches on the expression of antiinflammatory genes or acts indirectly to repress the activity of a number of distinct signaling pathways such as nuclear factor (NF)-κB and activator protein (AP)-1. This latter step requires the recruitment of corepressor molecules. Importantly, this latter interaction is mutually repressive in that high levels of NF-κB and AP-1 attenuate GR function. A failure to respond may therefore result from reduced GC binding to GR, reduced GR expression, enhanced activation of inflammatory pathways, or lack of corepressor activity. These events can be modulated by oxidative stress, T-helper type 2 cytokines, or high levels of inflammatory mediators, all of which may lead to a reduced clinical outcome. Understanding the molecular mechanisms of GR action, and inaction, may lead to the development of new antiinflammatory drugs or may reverse the relative steroid insensitivity that is characteristic of patients with these diseases.

Figures in this Article

Asthma currently affects 300 million people worldwide, and it is estimated that by 2025 a further 100 million people will be affected. Glucocorticoids (GCs) are highly effective in treating most inflammatory diseases, and, for example, asthma is controlled, to a greater or lesser extent, in the majority of patients by therapy with inhaled GC (ICS) therapy, either alone or in combination with long-acting β2-agonists (LABAs), with minimal or no side effects.1 Nevertheless, there is a small proportion of asthmatic patients, including present cigarette smokers and former cigarette smokers, who fail to respond to GCs even at high doses or with supplementary therapy.1 In part, the efficacy of ICSs lies in improving bronchial hyperresponsiveness, in reducing the eosinophilic and lymphocytic inflammation in the airway wall, and in suppressing the expression of multiple inflammatory genes in the airways.1 There is some evidence that ICS therapy may also reverse, to a certain extent, features of airway wall remodeling, such as basement membrane thickness.1Persons with asthma who smoke have an impaired response to therapy with both ICSs and oral GCs compared with persons with asthma who do not smoke.2 Smoking cessation improves basal lung function but requires at least a year to demonstrate any improvement in GC responsiveness with respect to morning peak expiratory flow, but not FEV1, after receiving therapy with high-dose prednisolone.,2

In addition, even high doses of GCs have a minimal effect on the inexorable decline in lung function in COPD patients and have only a small effect in reducing COPD exacerbations.3 This is consistent with the demonstration that therapy with ICSs or oral GCs fails to reduce the numbers of inflammatory cells, cytokines, chemokines, or proteases in induced sputum or airway biopsy specimens from patients with COPD.3 GCs are also ineffective at suppressing these inflammatory proteins in alveolar macrophages from COPD patients compared to cells from healthy smokers and nonsmokers.3 This appears to result from a defect in the antiinflammatory effect of GCs, since other antiinflammatory therapies, such as theophylline and resveratrol, have inhibitory effects.3 GC insensitivity, therefore, presents a profound management problem in persons with asthma who smoke, in patients with severe asthma, and in patients with COPD. These patients also account for a disproportionate amount of health-care costs.1,3

GC-resistant or corticosteroid-refractory (CSR) asthma is defined as < 15% improvement in baseline FEV1 after a 14-day course of oral prednisolone (40 mg/d) in patients who demonstrate > 15% improvement in FEV1 with salbutamol therapy.1 Furthermore, patients who showed improvements in FEV1 of ≥ 30% were considered to be GC-sensitive (CSS).,1 This definition has been used in subsequent studies. This definition of CSR asthma probably represents an extreme case, but these patients are useful as a comparison in studies elucidating the mechanisms underlying GC insensitivity in asthma patients. This definition of CSR asthma has been based on the reversibility of airflow obstruction to pharmacologic agents without any accompanying indication as to whether this group of patients is characterized by a particular clinical type, a pattern of asthma, or a specific pathophysiology. Further research in this area is essential, and recent data4 from the Severe Asthma Research Protocol has begun to address some of these issues. It is important to highlight here that these CSR patients are a subset of those patients with severe asthma and that the terms are not interchangeable, since some CSR patients do not have severe disease and some patients with severe asthma are not GC insensitive.4

Some pathologic characteristics of patients with CSR asthma are becoming clear. The thickness of the airway epithelium and basement membrane in patients with CSR asthma is greater than those in patients with CSS asthma, with both groups showing similar levels of epithelial shedding.56 This difference was associated with an altered expression of markers of epithelial proliferation (eg, increased Ki-67 expression, reduced retinoblastoma expression, and reduced expression of Bcl-2 protein, which is a negative regulator of epithelial cell death).,5 The failure of ICS therapy to induce the expression of tissue inhibitor of metalloproteinase-1 in CSR asthmatic patients has been proposed7 to account, at least in part, for this increase in airway remodeling.

Recently, a number of unbiased techniques, such as the hierarchical clustering of BAL cytokine expression8and the analysis of volatile organic components of exhaled breath using an electronic nose,9 have been used to provide a fingerprint of distinct phenotypes of patients with CSR asthma. Interestingly, in the former study the expression of key cytokines such as interleukin (IL)-2 and IL-4 were associated with the lack of GC responsiveness, which was similar to the findings of earlier studies of biopsy samples from Ito and colleagues and references therein.1 Some studies3,1012 have been performed comparing patients with COPD to healthy smokers, but, as with patients with CSR asthma, further studies using age-matched, disease-severity control subjects in larger groups of patients are needed to determine the usefulness of this approach.

Most of the studies examining patients with CSR asthma have been limited due to the examination of only a few persons, generally 6 to 12 subjects, in each patient group. Furthermore, few details have been provided as to the type of asthma these patients had, apart from their baseline FEV1 and their response to oral prednisolone.

GCs act by binding to and activating specific cytosolic GC receptors (GRs), which are held in a resting state by a number of chaperone proteins (Fig 1 ). These activated GRs then have to translocate into the nucleus before they can regulate inflammatory gene expression.1 Once in the nucleus, the activated GR can induce the expression of a number of key antiinflammatory genes following a direct association with DNA at GC response elements (GREs) in the promoter regions of these genes. Alternatively, the activated GR can selectively repress the transcription of specific inflammatory genes without binding to DNA itself but by a number of pleiotropic actions at the promoters of inflammatory genes (Fig 1). Inflammatory genes are regulated by the actions of proinflammatory transcription factors such as nuclear factor (NF)-κB, activator protein (AP)-1, and signal transducer and activator of transcription proteins. Activated GR binds to these transcription factors, either directly or indirectly, and recruits corepressor proteins that blunt the ability of these transcription factors to switch on inflammatory genes.,1 Importantly, these actions are mutually inhibitory. Thus, the variety of mechanistic actions of GR may underlie their effectiveness, but this suggests that the abnormal activation of other signaling pathways that are targets for GR or otherwise impinge on, and reverse, GR action may result in GC refractoriness.

GR is a phosphoprotein and changes in its phosphorylation pattern may affect all aspects of its function.13The human GR has five phosphorylation sites (Ser113, Ser141, Ser203, Ser211, and Ser226) within its activation domain. The phosphorylation of these sites can be ligand dependent or ligand independent. Newly synthesized GR is hyperphosphorylated at three major sites (Ser203, Ser211, and Ser226), but once within the heat shock protein 90 (hsp90)-containing chaperone complex this phosphorylation is reduced to a basal state by the presence of phosphatases such as protein phosphatase 5. Agonist binding causes dissociation of the hsp90 complex and a loss of phosphatase activity, allowing GR phosphorylation to increase at selective serine residues.14 This increase in GR phosphorylation is not seen with antagonist binding.14

GR phosphorylation has been associated with the modulation of ligand binding, nuclear translocation, DNA binding, receptor dimerization, and interaction with general transcription factors.13,15 For example, GR phosphorylation can alter its transcriptional activity in a promoter-dependent context, since the mutation of these serine residues affects some GRE reporter genes but not others.13,15 Furthermore, in lung epithelial cells the degree of Ser211 phosphorylation correlates with ligand binding, nuclear translocation, and GR transactivation.5,13 These phosphoisoforms are selectively recruited to GREs within distinct target genes with differing time courses16 and thereby coordinate the expression of characteristic patterns of gene expression. The ability of Ser211 phosphorylation to alter cofactor/corepressor activity may also account for changes in gene expression patterns.13,15

These phosphorylation sites are also selectively targeted by mitogen-activated protein kinases (MAPKs), cyclin-dependent kinase (CDK), glycogen synthase kinase-3, and c-Jun N-terminal kinases (JNKs).13,15 In neuronal cells, CDK5 phosphorylates GR at multiple serine sites, including Ser203 and Ser211, and suppresses GR transactivation in a gene-selective and tissue-selective manner by attenuating coactivator recruitment.17 In addition, the direct phosphorylation of the rat GR by JNK on Ser246 (identical to Ser226 in human GR) attenuates GR function.13,15

In contrast, the direct phosphorylation of GR by p38 MAPK remains controversial. The activation of p38 MAPK in the HeLa cells impairs GR activation through an effect on the ligand-binding domain. However, mutation of the MAPK did not affect p38 MAPK actions, suggesting an indirect effect on GR function, possibly through a downstream kinase or the effects on GR chaperone proteins or coactivators.18In contrast, in human and mouse lymphoid cells, p38 MAPK has been reported19 to increase Ser211 phosphorylation and to enhance GR-mediated apoptosis. Interestingly, in contrast to studies17 in other cell types, the mutation of Ser211 enhanced GR-mediated transactivation in neuronal cells, highlighting the stimulus-, cell-, and species-specific nature of these events. This may reflect the effect of CDK5 phosphorylation of GR-associated coactivators or basal factors present in distinct cell types.

At a molecular level, resistance to the antiinflammatory effects of GC can be induced by several mechanisms, which may differ between patients. The reduction in the GC responsiveness observed in cells from patients with CSR asthma, asthma patients who smoke, and patients with COPD has been variably ascribed to reduced GR expression, the altered affinity of the ligand for GR, the reduced ability of the GR to bind to DNA, the reduced expression and/or activity of corepressor proteins, or the increased expression of inflammatory transcription factors, such as NF-κB and AP-11(Fig 1). Furthermore, unlike familial GC resistance, in which there are mutations in GR and a subsequent resetting of the basal cortisol level, these CSR patients have normal cortisol levels and do not have Addison disease.1

Certain cytokines, particularly IL-2, IL-4, and IL-13, which are overexpressed in BAL fluid and bronchial biopsy specimens of patients with CSR asthma,8 and the exposure of peripheral blood mononuclear cells from sensitized individuals exposed to cat allergen in vitro20 reduce GR ligand binding affinity in T lymphocytes, resulting in local resistance to the antiinflammatory actions of GCs.,1 These changes occur in the nucleus and are reversed by serum deprivation.1 This GR affinity abnormality probably reflects, therefore, a specific inflammatory subtype seen within the CSR subgroup of patients with severe asthma.1 These changes in binding affinity and subsequent nuclear import may reflect increases in the expression of the dominant negative isoform of GR, GRβ, which can affect GRα function in BAL fluid cells from patients with CSR asthma following knockdown with short-interference RNA.20

GR phosphorylation can be induced by IL-2/IL-4 and by IL-13 in a p38 MAPK-mediated process, leading to a loss of GR function.21 Depending on the stimulus used, other MAPKs or kinase pathways may also regulate GR function (eg, GC insensitivity induced in T cells by coreceptor activation or superantigen is reversed by inhibitors of the extracellular signal-regulated kinase MAPK pathway).,1 In the case of superantigen exposure, extracellular signal-regulated kinase activation may also lead to an increase in the expression of GRβ. In murine cells, IL-2 alone can modulate GR responsiveness under the control of Janus kinase-3/signal transducer and activator of transcription (or STAT)-5.20

Furthermore, enhanced growth factor-associated phosphotyrosine levels in patients with CSR asthma are not affected by ICS therapy and may contribute to persistent, GC-unresponsive inflammation in patients with severe asthma.22 Finally, kinases such as the phosphoinositide 3-kinases (PI-3Ks) may also affect GR responsiveness through the modulation of GR cofactors rather than by GR itself (see next section). Often, however, the exact mechanism of kinase action on GR function in patients with CSR asthma is not clear.1,13

GR nuclear translocation is defective in a subset of patients with CSR asthma,1 leading to a loss of GR-GRE DNA binding.1 Cigarette smoke in addition to containing > 4,000 noxious chemicals also contains > 1015 reactive oxygen species per puff.,23 Increased levels of oxidative stress are not only seen in COPD patients and asthma patients who smoke, but also in patients with severe asthma and in asthma patients who smoke.23 Importantly, studies23 in many different types of cells have shown that the presence of antioxidants is able to restore GR functions, including nuclear translocation, that were reduced in response to cigarette smoke or other oxidative stresses. Drugs such as LABAs that enhance GR nuclear translocation may also prove to be effective add-on agents in patients with CSR lung diseases.1

High levels of nitric oxide (NO) have been reported in patients with CSR asthma, and this may cause GR nitrosylation at an hsp90 interaction site, thereby modifying ligand binding.1 Smoking not only induces high levels of oxidative stress but reduces the production of exhaled NO, possibly due to the conversion of NO to peroxynitrate, which can induce GC insensitivity.23NO synthase (NOS)-2 inhibitors have recently been shown24 to be safe, but ineffective, in treating patients with mild asthma, but they may play an important role in the treatment of patients with CSR asthma, in patients with asthma who smoke, and in COPD patients.23

Changes in GR-GRE binding have also been associated with the excessive activation of AP-1, increased c-Fos expression, and JNK activity in response to inflammatory stimuli, such as T helper type 2 cytokines and tumor necrosis factor (TNF)-α.1,25 Furthermore, prednisolone (40 mg/d for 2 weeks) did not affect the numbers of phospho-c-Jun and activated JNK-positive cells.25 It is unclear whether increased c-Fos expression and JNK activation is a primary or secondary defect caused by the excessive production of a unique pattern of cytokines in the airways of asthmatic patients.

NF-κB and AP-1 are redox-sensitive proteins whose activity is induced by oxidative stress and cigarette smoke, potentially leading to an induction of GC unresponsiveness.23 Thus, the heightened inflammation seen in response to oxidative stress may then fail to respond to GCs.23 At present, there is no evidence for a genetic component leading to enhanced AP-1 activation in patients with CSR asthma,1 although evidence26 does implicate NF-κB in patients with CSR asthma. The inhibition of JNK or the NF-κB-activating kinase IKK2 by selective inhibitors may therefore restore GC responsiveness in these patients.1

GRβ acts within the nucleus as a dominant negative isoform of GRα with respect to both gene induction and gene repression.1 If GRα nuclear translocation is reduced in blood cells and BAL fluid macrophages, as has been described in some patients with CSR asthma1 and in asthma patients who smoke,27 the relative ratio in the nucleus may change greatly at specific gene promoters and may account for the GR inefficacy observed in these patients.23 The loss of GR transactivation, possibly due to reduced GR-GRE binding, may lead to a loss of dual MAPK phosphatase-1 expression in CSR asthma which would limit the ability to overcome p38 MAPK and JNK activation.28 Thus, changes in p38/MAPK phosphatase-1 homeostasis may be important in contributing to GC insensitivity.

Recurrent exacerbations are a major cause of morbidity and medical expenditures in patients with asthma, and rhinoviral infection can reduce GR nuclear translocation and reduce GR function.1 Therapeutic interventions aimed at treating viral or bacterial infections may reduce morbidity and medical expenditures in these patients.

Within the nucleus, GR is able to recruit corepressor proteins such as histone deacetylase (HDAC) 2 to actively transcribing gene complexes, which in turn results in the suppression of proinflammatory genes.1 Some patients with CSR asthma demonstrate no loss of nuclear translocation and no defect in the side-effect profile, but a loss in antiinflammatory properties.1 This may reflect a reduced ability of GR to associate with HDAC2 or Brahma-related gene 1.2930 Brahma-related gene 1 is absent in many cases of GC-insensitive corticotrophic adenocarcinomas found in subjects with Cushing disease.30

HDAC2 activity is reduced in BAL fluid macrophages from smokers and inversely correlates with GC sensitivity.29 HDAC2 expression and activity are further reduced in BAL fluid macrophages, bronchial biopsy specimens, and peripheral lung tissue from patients with COPD,31and in the peripheral blood cells of asthmatic patients who smoke compared to nonsmokers.32 Importantly, the overexpression of HDAC2 in GC-insensitive BAL fluid macrophages obtained from COPD subjects restored GC responsiveness; conversely, the suppression of HDAC2 expression using RNA interference in BAL fluid macrophages from healthy subjects attenuated GC sensitivity.29 The suppression of HDAC2 activity may be due to tyrosine nitration, implicating a potential therapeutic role for antioxidants23or NOS-2 inhibitors24 in restoring GC responsiveness, as was described above.

The antiinflammatory effects of theophylline in patients with severe asthma and COPD may be mediated via the enhancement of HDAC2 activity through a mechanism that is independent of its bronchodilator actions or inhibitory effects on phosphodiesterase-4 activity.32 Theophylline activates HDAC2 preferentially under conditions of oxidative stress and potentiates the antiinflammatory effects of GCs in vitro. This may explain why adding a low dose of theophylline is more effective than increasing the dose of ICSs in patients whose disease is not adequately controlled and why theophylline withdrawal worsens disease control in patients with severe asthma.,32The exact mechanism whereby theophylline and other agents activate HDAC2 is not yet certain but may be through an effect on PI-3K.33 Intriguingly, mice that express a PI-3Kδ kinase dead mutant are able to respond to budesonide following cigarette smoking, whereas budesonide is ineffective in wild-type animals.33 In addition, the knockdown of PI-3Kδ in human peripheral blood cells prevents oxidative stress from inducing GC insensitivity.33

The treatment of regulatory T cells from subjects with CSR asthma with vitamin D3 in combination with dexamethasone can restore the ability of these cells to release IL-10 up to levels similar to those seen in cells from CSS patients.34 This, in turn, allowed IL-10 to up-regulate GR expression and reverse the dexamethasone-induced reduction in GR expression. Impressively, the oral administration of vitamin D3 (0.5 μg/d) for 7 days to patients with CSR asthma enhanced ex vivo regulatory T-cell responses to dexamethasone.,34 This suggests that vitamin D3 therapy could potentially increase the therapeutic response to GCs in patients with CSR asthma.

Many of these CSR asthma patients are not completely unresponsive to GCs but will respond to much higher doses than normal with the corollary that the side effects are increased; the introduction of ICSs with a better safety profile, such as ciclesonide, may enable higher topical doses to be administered to these patients with reduced GC side effects35 (Table 1 ). Alternatively, the multiple mechanisms underlying CSR asthma may indicate the need for patient-specific treatment with novel therapies directed at abnormal signaling pathways to restore asthma control,1(Table 1). For example, treatment with anti-IgE therapy in a small cohort of these CSR patients has shown36 clinical effectiveness, although the cost-effectiveness of this treatment is under debate.

Antibodies or antagonists directed against IL-2/IL-4 may be effective in CSR asthma as seen with anti-IL-2 in CSR patients with inflammatory bowel disease.1 MAPK activities have been shown to be associated with CSR asthma in some patients by affecting GC function in a stimulus-dependent manner.1 Many companies are developing drugs against kinases, and combination therapy with p38 MAPK or JNK inhibitors may prove to be effective steroid-sparing agents.1 In addition, better antioxidants may prove to be effective in some patients.23 Genetic studies implicate the NF-κB pathway in CSR asthma26 and small molecule inhibitors targeting this pathway are in clinical development.37

Although the development of antieosinophil biological agents was set back by the lack of efficacy of anti–IL-5 seen in patients with mild-to-moderate asthma,38 it is possible that they may be effective in some patients with CSR asthma in whom airway remodeling may be important.38 Furthermore, in some patients with airway neutrophilia who are corticosteroid insensitive, C-X-C chemokine receptor-1/2 antagonists or biological agents may be effective, particularly in the treatment of severe exacerbations.32,39Interestingly, clarithromycin can reduce IL-8 levels and sputum neutrophilia, and improve asthma quality of life in patients with refractory noneosinophilic asthma.40 This macrolide treatment may reflect a novel approach to treatment, particularly in patients with < 3% sputum eosinophilia.

Other approaches that may prove useful in the future for the treatment of CSR asthma include the administration of antiinflammatory cytokines such as IL-10 or the induction of IL-10–secreting regulatory T cells by vitamin D3 in combination with a GC, inhibitors of phosphodiesterase-4, Janus kinase-3, or anti–IL-1 therapies.1 Antileukotrienes (montelukast, 10 mg/d for 4 weeks) have been tested in patients with CSR asthma, in whom they did not prevent sputum eosinophilia, but montelukast did have a greater effect on lung function than ICSs in asthma patients who smoke.41However, the endogenous antiinflammatory eicosanoid lipoxin A4 (LXA4) is reduced in patients with CSR asthma,42 and this suggests that LXA4 therapy may be effective in these patients.

In small studies,43 patients with CSR asthma who failed to respond to conventional therapy were able to respond to anti–TNF-α therapy with improved lung function. This was particularly the case with etanercept, a soluble TNF-α receptor blocker, in patients who had high levels of surface TNF-α on peripheral blood cells.43These results promised a new treatment regime for these patients; however, a larger study44 using anti–TNF-α has recently been stopped due to the high incidence of sepsis (Jean Bousquet, MD; personal communication; March 2007). In addition, anti–TNF-α does not appear to be effective in treating COPD,44 and no information is available for asthma patients who smoke.

Most patients with asthma are successfully treated with conventional therapy. Nevertheless, there is an increasingly smaller proportion of asthmatic patients, including present smokers and ex-smokers, who fail to respond to high-dose GC treatment alone or with the addition of supplementary therapy. These patients account for a disproportionate amount of health-care costs. In addition, patients with COPD are unresponsive to GC therapy to a great extent.

There are several potential approaches that can be taken to treat these CSR patients. Those who smoke should be encouraged to quit smoking as this can restore GC sensitivity to some aspects of the inflammatory response. The type of inflammation in these patients may be distinct, and targeting this inflammation with selective therapeutic agents may be beneficial. An alternative approach is to try to restore GC sensitivity rather than prevent inflammation per se. Increasing knowledge of the molecular mechanisms by which these patients lose responsiveness to GCs opens up the possibility of defined patient-specific therapy. Not all patients with CSR asthma and patients with asthma and COPD who smoke are necessarily insensitive to GC for the same reason; some drugs will, therefore, be more effective than others in each subgroup of patients. Rapid tests that distinguish some of these molecular defects in cells from these patients may make the advent of selective therapy closer and more effective. Novel potent antiinflammatory therapies that are aimed at reducing the need for therapy with systemic GCs in these patients are urgently needed in order to improve their quality of life.

Abbreviations: AP = activator protein; CDK = cyclin-dependent kinase; CSR = corticosteroid refractory; CSS = corticosteroid sensitive; GC = glucocorticoid; GR = glucocorticoid receptor; GRE = glucocorticoid response element; HDAC = histone deacetylase; hsp90 = heat shock protein 90; ICS = inhaled glucocorticoid; IL = interleukin; JNK = c-Jun N-terminal kinase; LABA = long-acting β2-agonist; LXA4 = lipoxin A4; MAPK = mitogen-activated protein kinase; NF = nuclear factor; NO = nitric oxide; NOS = nitric oxide synthase; PI-3K = phospho-inositol-3 phosphate kinase; TNF = tumor necrosis factor

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Figure Jump LinkFigure 1. Mechanism of GC action by the GR and sites of regulation in GC insensitivity. GCs freely diffuse from the circulation across cell membranes where they interact with the GR. On ligand binding, the receptor is activated, released from a chaperone complex, and translocates to the nucleus where it can bind as a dimer to GRE and induce gene transcription (transactivation). Alternatively, GCs may act by inhibiting the ability of other transcription factors such as NF-κB and AP-1 activated by cytokines to induce proinflammatory gene transcription. In this instance, GR acts as a monomer and recruits repressor proteins such as HDAC2. The activation of kinase pathways by inflammatory mediators or T-cell receptor coactivation (CD3/CD28) can attenuate GR function by reducing ligand binding and nuclear translocation, or by mutually suppressing/interacting with NF-κB or AP-1. Allergens and superantigens can also affect GR ligand binding but are also able, along with T helper type 2 cytokines, to induce GRβ. Cigarette smoke and reactive oxygen species (ROS) stress can prevent GR nuclear translocation or reduce the activity of HDAC2 reducing the ability of GR to switch off inflammatory genes. Drugs such as LABAs can enhance GR nuclear translocation, whereas theophylline can enhance HDAC2 activity. These different actions may account for their ability to improve GR function in disease. IKK = inhibitor of NF-κB kinase; RE = response element.Grahic Jump Location
Table Graphic Jump Location
Table 1. Potential Therapies To Overcome Glucocorticoid Resistance in Severe Asthma and COPD*
* 

Ab = antibody.

The authors thank the members of the Airways Disease Section, National Heart and Lung Institute, for helpful discussions. The literature in this area is expanding considerably, and, due to constraints on the number of references in this article, we were unable to cite all original manuscripts.

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Barnes, PJ New molecular targets for the treatment of neutrophilic diseases.J Allergy Clin Immunol2007;119,1055-1062. [PubMed]
 
Marwick, JA, Ito, K, Adcock, IM, et al Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy.Expert Opin Ther Targets2007;11,745-755. [PubMed]
 
Xystrakis, E, Kusumakar, S, Boswell, S, et al Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.J Clin Invest2006;116,146-155. [PubMed]
 
Bateman, ED, Linnhof, AE, Homik, L, et al Comparison of twice-daily inhaled ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma.Pulm Pharmacol Ther2008;21,264-275. [PubMed]
 
Wu, AC, Paltiel, AD, Kuntz, KM, et al Cost-effectiveness of omalizumab in adults with severe asthma: results from the Asthma Policy Model.J Allergy Clin Immunol2007;120,1146-1152. [PubMed]
 
Adcock, IM, Chung, KF, Caramori, G, et al Kinase inhibitors and airway inflammation.Eur J Pharmacol2006;533,118-132. [PubMed]
 
Simon, HU Cytokine and anti-cytokine therapy for asthma.Curr Allergy Asthma Rep2006;6,117-121. [PubMed]
 
Qiu, Y, Zhu, J, Bandi, V, et al Bronchial mucosal inflammation and upregulation of CXC chemoattractants and receptors in severe exacerbations of asthma.Thorax2007;62,475-482. [PubMed]
 
Simpson, JL, Powell, H, Boyle, MJ, et al Clarithromycin targets neutrophilic airway inflammation in refractory asthma.Am J Respir Crit Care Med2008;177,148-155. [PubMed]
 
Lazarus, SC, Chinchilli, VM, Rollings, NJ, et al Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma.Am J Respir Crit Care Med2007;175,783-790. [PubMed]
 
Celik, GE, Erkekol, FO, Miotasiotarliotagil, Z, et al Lipoxin A(4) levels in asthma: relation with disease severity and aspirin sensitivity.Clin Exp Allergy2007;37,1494-1501. [PubMed]
 
Berry, MA, Hargadon, B, Shelley, M, et al Evidence of a role of tumor necrosis factor α in refractory asthma.N Engl J Med2006;354,697-708. [PubMed]
 
Rennard, SI, Fogarty, C, Kelsen, S, et al The safety and efficacy of infliximab in moderate-to-severe chronic obstructive pulmonary disease.Am J Respir Crit Care Med2007;175,926-934. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Mechanism of GC action by the GR and sites of regulation in GC insensitivity. GCs freely diffuse from the circulation across cell membranes where they interact with the GR. On ligand binding, the receptor is activated, released from a chaperone complex, and translocates to the nucleus where it can bind as a dimer to GRE and induce gene transcription (transactivation). Alternatively, GCs may act by inhibiting the ability of other transcription factors such as NF-κB and AP-1 activated by cytokines to induce proinflammatory gene transcription. In this instance, GR acts as a monomer and recruits repressor proteins such as HDAC2. The activation of kinase pathways by inflammatory mediators or T-cell receptor coactivation (CD3/CD28) can attenuate GR function by reducing ligand binding and nuclear translocation, or by mutually suppressing/interacting with NF-κB or AP-1. Allergens and superantigens can also affect GR ligand binding but are also able, along with T helper type 2 cytokines, to induce GRβ. Cigarette smoke and reactive oxygen species (ROS) stress can prevent GR nuclear translocation or reduce the activity of HDAC2 reducing the ability of GR to switch off inflammatory genes. Drugs such as LABAs can enhance GR nuclear translocation, whereas theophylline can enhance HDAC2 activity. These different actions may account for their ability to improve GR function in disease. IKK = inhibitor of NF-κB kinase; RE = response element.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Potential Therapies To Overcome Glucocorticoid Resistance in Severe Asthma and COPD*
* 

Ab = antibody.

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Marwick, JA, Ito, K, Adcock, IM, et al Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy.Expert Opin Ther Targets2007;11,745-755. [PubMed]
 
Xystrakis, E, Kusumakar, S, Boswell, S, et al Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.J Clin Invest2006;116,146-155. [PubMed]
 
Bateman, ED, Linnhof, AE, Homik, L, et al Comparison of twice-daily inhaled ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma.Pulm Pharmacol Ther2008;21,264-275. [PubMed]
 
Wu, AC, Paltiel, AD, Kuntz, KM, et al Cost-effectiveness of omalizumab in adults with severe asthma: results from the Asthma Policy Model.J Allergy Clin Immunol2007;120,1146-1152. [PubMed]
 
Adcock, IM, Chung, KF, Caramori, G, et al Kinase inhibitors and airway inflammation.Eur J Pharmacol2006;533,118-132. [PubMed]
 
Simon, HU Cytokine and anti-cytokine therapy for asthma.Curr Allergy Asthma Rep2006;6,117-121. [PubMed]
 
Qiu, Y, Zhu, J, Bandi, V, et al Bronchial mucosal inflammation and upregulation of CXC chemoattractants and receptors in severe exacerbations of asthma.Thorax2007;62,475-482. [PubMed]
 
Simpson, JL, Powell, H, Boyle, MJ, et al Clarithromycin targets neutrophilic airway inflammation in refractory asthma.Am J Respir Crit Care Med2008;177,148-155. [PubMed]
 
Lazarus, SC, Chinchilli, VM, Rollings, NJ, et al Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma.Am J Respir Crit Care Med2007;175,783-790. [PubMed]
 
Celik, GE, Erkekol, FO, Miotasiotarliotagil, Z, et al Lipoxin A(4) levels in asthma: relation with disease severity and aspirin sensitivity.Clin Exp Allergy2007;37,1494-1501. [PubMed]
 
Berry, MA, Hargadon, B, Shelley, M, et al Evidence of a role of tumor necrosis factor α in refractory asthma.N Engl J Med2006;354,697-708. [PubMed]
 
Rennard, SI, Fogarty, C, Kelsen, S, et al The safety and efficacy of infliximab in moderate-to-severe chronic obstructive pulmonary disease.Am J Respir Crit Care Med2007;175,926-934. [PubMed]
 
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