Glucocorticoid suppression of nuclear factor-κB: a role for histone modifications

Kagoshima, Masahiko; Ito, Kazuhiro; Cosío, Borja G.; Adcock, Ian M.

doi:10.1042/bst0310060

Cited by 52 publications

(33 citation statements)

References 51 publications

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“…24,25 Another route related to the modulation of apoptosis by glucocorticoids is through NF-kB, a transcription factor induced by proinflammatory cytokines. 26,27 A persistent activation of the NF-kB/IkB system might represent one of the mechanisms by which PBT apoptosis is reduced. 8 Although there is some controversy about the role of this transcription factor in cell apoptosis, most data support an NF-kB antiapoptotic action.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma

Pace¹,

Gagliardo²,

Melis³

et al. 2004

Journal of Allergy and Clinical Immunology

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Background: In asthma T cells are characterized by an increased activation state and by reduced apoptosis. Objective: Because the clinical efficacy of inhaled corticosteroids combined with long-acting b 2 -agonists has been widely demonstrated in asthma, we studied, in vitro, the effect of fluticasone propionate (FP) and salmeterol alone and in combination on the activation and apoptosis of peripheral blood T cells (PBTs), on the expression of phosphorylated nuclear factor kB inhibitor (IkBa), and on the nuclear translocation of glucocorticoid receptor (GR) in PBTs from asthmatic subjects. Methods: Apoptosis was evaluated on the basis of annexin V binding, whereas the expression of caspases 8 and 3 and phosphorylated IkBa, as well as the nuclear translocation of the GR, were evaluated by means of Western blot analysis. Results: FP alone increases and salmeterol alone does not affect T-cell apoptosis. The combination of FP and salmeterol significantly increases PBT apoptosis in comparison with FP alone. FP at the lower concentration, when combined with salmeterol, is equivalent to FP at the higher concentration in inducing PBT apoptosis. The synergy in the induction of cell apoptosis is associated with more efficient activation of caspases 8 and 3. FP plus salmeterol is also able to synergistically reduce the expression of phosphorylated IkBa, thus limiting nuclear factor kB activation. The synergy was related to an increased nuclear translocation of the GR. Conclusion: This study shows that the combination of FP and salmeterol is able to control PBT activation in asthmatic patients more efficiently than FP alone and with a lower concentration of

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Section: Discussionmentioning

confidence: 99%

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma

Pace¹,

Gagliardo²,

Melis³

et al. 2004

Journal of Allergy and Clinical Immunology

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“…We found it was induced in Th17 cells by Dex (Table S1). Therefore, the persistence of NFKBIZ in Dex-treated human Th17 cells (Table S1) could be key to their maintenance of RORC expression (20) and may also interfere with GR function (21,22). In addition, recent reports of genome-wide binding profiles have demonstrated the transcription factors NF-κB and Stat3, both of which are activated in Th17 cells, may antagonize GR functions by changing the DNA binding sites of GR (23).…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

Schewitz-Bowers

Lait

Copland

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients’ glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual’s disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

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“…For example, the transcriptional induction of GM-CSF, IL-8, TNF-␣, or RANTES is dependent on the activation of IB kinase NF-B, which binds to and activates coactivator molecules through the acetylation of core histones, leading to increased cytokine gene transcription (12)(13)(14). Corticosteroids are likely to inhibit the expression of these cytokines through the reversal of histone acetylation at the site of the cytokine gene expression by direct binding of the activated corticosteroid receptor to NF-Bassociated coactivators or by recruitment of HDACs to the activated transcription complex (15,16). There was no difference in the spontaneous release or in the LPS-stimulated release of these cytokines between patients with severe and patients with nonsevere asthma, indicating that the differences in steroid sensitivity observed were not related to a greater expression of cytokines, probably reflecting no differences in intracellular signaling induced by LPS between the two groups.…”

Section: Discussionmentioning

confidence: 99%

Relative Corticosteroid Insensitivity of Peripheral Blood Mononuclear Cells in Severe Asthma

Hew

Bhavsar

Torrego

et al. 2006

Am J Respir Crit Care Med

244

145

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Glucocorticoid suppression of nuclear factor-κB: a role for histone modifications

Cited by 52 publications

References 51 publications

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma

Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A

Relative Corticosteroid Insensitivity of Peripheral Blood Mononuclear Cells in Severe Asthma

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