Update on glucocorticoid action and resistance

Ito, Kazuhiro; Chung, Kian Fan; Adcock, Ian M.

doi:10.1016/j.jaci.2006.01.032

Cited by 350 publications

(332 citation statements)

References 230 publications

(323 reference statements)

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“…Corticosteroids belong to the family of 21-carbon steroid nuclear hormones [1] and act by binding to the ubiquitously expressed glucocorticoid receptor (GR) which is predominantly localised to the cytoplasm. Corticosteroids freely diffuse from the circulation across the cell membrane into cells and bind to cytoplasmic GR inducing a conformational change in the receptor, loss of its chaperone proteins and its nuclear localisation.…”

Section: Molecular Mechanisms Of Corticosteroidsmentioning

confidence: 99%

“…Maximum inflammatory gene expression probably requires that a number of transcription factors act together in a coordinated manner, and glucocorticoids, by targeting several transcription factors, might have greater effects than if only a single factor was targeted. The precise mechanism for this repression may include binding and recruiting nuclear receptor corepressors such as NCoR and HDACs, direct repression of coactivator complexes, or effects on RNA polymerase II phosphorylation [7,8]. For example, in primary airway smooth-muscle cells, fluticasone attenuates TNF-α-induced histone H4 acetylation leading to a reduction in p65 association with the native CCL11 promoter and suppression of CCL11 expression [9].…”

Section: Molecular Mechanisms Of Corticosteroidsmentioning

confidence: 99%

“…For example, in primary airway smooth-muscle cells, fluticasone attenuates TNF-α-induced histone H4 acetylation leading to a reduction in p65 association with the native CCL11 promoter and suppression of CCL11 expression [9]. In addition, glucocorticoids might play a role in repressing the action of MAPKs, such as the extracellular signal-regulated kinase (ERK), p38 MAPK, and c-Jun N-terminal kinase (JNK) [2,7,8]. These actions are mutually inhibitory and, in the case of p38 and JNK, may relate to induction of the dual-specificity MAPK phosphatase 1 (MKP-1), which thereby attenuates MAPK activation [10].…”

Section: Molecular Mechanisms Of Corticosteroidsmentioning

confidence: 99%

“…These actions are mutually inhibitory and, in the case of p38 and JNK, may relate to induction of the dual-specificity MAPK phosphatase 1 (MKP-1), which thereby attenuates MAPK activation [10]. Importantly, p38 MAPK-mediated GR phosphorylation can attenuate GR function [7,11].…”

Section: Molecular Mechanisms Of Corticosteroidsmentioning

confidence: 99%

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Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Chung

Caramori

Adcock

2009

Eur J Clin Pharmacol

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123

106

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International audienceInhaled corticosteroid (ICS) therapy in combination with long-acting β-adrenergic agonists represents the most important treatment for chronic airways diseases such as asthma and chronic obstructive pulmonary disease (COPD). ICS therapy forms the basis for treatment of asthma of all severities, improving asthma control, lung function and preventing exacerbations of disease. Use of ICS has also been established in the treatment of COPD, particularly symptomatic patients, who experience useful gains in quality of life, likely from an improvement in symptoms such as breathlessness and in reduction in exacerbations, and an attenuation of the yearly rate of deterioration in lung function. The addition of long-acting β-agonist (LABA) therapy with ICS increases the efficacy of ICS effects in moderate-to-severe asthma. Thus, a 800 μg daily dose of the ICS budesonide reduced severe exacerbation rates by 49% compared to a low dose of 200 μg daily, and addition of the LABA formoterol to budesonide (800 μg) led to a 63% reduction. In COPD, the effects of ICS are less prominent but there are beneficial effects on the decline in FEV and the rate of exacerbations. A reduction in the rate of decline in FEV of 16 ml/year with a 25% reduction in exacerbation rate has been reported with the salmeterol and fluticasone combination. A non-significant 17.5% reduction in all-cause mortality rate with ICS and LABA is reported. Chronic inflammation is a feature of both asthma and COPD, although there are site and characteristic differences. ICS targets this inflammation although this effect of ICS is less effective in patients with severe asthma and with COPD; however, addition of LABA may potentiate the anti-inflammatory effects of ICS. An important consideration is the presence of corticosteroid insensitivity in these patients. Currently available ICS have variably potent binding activities to specific glucocorticoid receptors, leading to inhibition of gene expression by either binding to DNA and inducing anti-inflammatory genes or by repressing the induction of pro-inflammatory mediators. Local side effects of ICS include oral candidiasis, hoarseness and dysphonia, while systemic side effects, such as easy bruising and reduction in growth velocity or bone mineral densitometry, are usually restricted to doses above maximally recommended doses. Use of LABA alone in patients with asthma increases the risk of asthma-related events including deaths, but this is less observed with the combination of ICS and LABA. Therefore, use of LABA alone is not recommended for asthma therapy. Future progress in ICS development will be characterised by the introduction of ICS with greater efficacy with a limited side-effect profile, and by longer-acting ICS that can be used in combination with once-daily LABAs. Other agents that could improve the efficacy of corticosteroids or reverse corticosteroid insensitivity may be added to ICS. ICS in combination with LABAs will continue to remain the main focus of treatment of airways diseases

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Section: Molecular Mechanisms Of Corticosteroidsmentioning

confidence: 99%

Section: Molecular Mechanisms Of Corticosteroidsmentioning

confidence: 99%

Section: Molecular Mechanisms Of Corticosteroidsmentioning

confidence: 99%

Section: Molecular Mechanisms Of Corticosteroidsmentioning

confidence: 99%

See 2 more Smart Citations

Inhaled corticosteroids as combination therapy with β-adrenergic agonists in airways disease: present and future

Chung

Caramori

Adcock

2009

Eur J Clin Pharmacol

Self Cite

123

106

View full text Add to dashboard Cite

show abstract

“…Corticosteroids are the most effective anti-inflammatory agents and topical corticosteroids including budesonide are the recommended therapy by current guidelines for asthma treatment [13]. Corticosteroids act on Tregs increasing IL-10 production [14] and enhancing IL-10 Treg function [5].…”

Section: Introductionmentioning

confidence: 99%