Persistent Activation of Nuclear Factor–κB Signaling Pathway in Severe Uncontrolled Asthma

Gagliardo, Rosalia; Chanez, Pascal; Mathieu, Marc; Bruno, Andreina; Costanzo, Giorgia; Gougat, Claire; Vachier, Isabelle; Bousquet, Jean; Bonsignore, G; Vignola, Antonio M.

doi:10.1164/rccm.200205-479oc

Cited by 163 publications

(135 citation statements)

References 45 publications

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“…1,2,8 In addition to the evidence of enhanced NF-kB activity in peripheral blood mononuclear cells of asthmatic patients, 9 our previous studies also demonstrated that NF-kB signal transduction, p38 MAPK and extracellular signal-regulated kinase (ERK) pathways played pivotal roles in regulating IL-3, IL-5 and granulocyte macrophage colonystimulating factor-induced intercellular adhesion molecule (ICAM)-1 expression and Th17 cytokine-elicited cytokine production from human eosinophils. 10,11 In an attempt to further investigate the activation of eosinophils induced by IL-33, we elucidated the intracellular signaling mechanisms regulating the survival, adhesion, and cytokine and chemokine release from eosinophils activated by IL-33, and we compared the effects of two other structurally and functionally related IL-1 family cytokines, IL-1b and IL-18.…”

Section: Introductionmentioning

confidence: 75%

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

et al. 2009

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The novel interleukin (IL)-1 family cytokine IL-33 has been shown to activate T helper 2 (Th2) lymphocytes, mast cells and basophils to produce an array of proinflammatory cytokines, as well as to mediate blood eosinophilia, IgE secretion and hypertrophy of airway epithelium in mice. In the present study, we characterized the activation of human eosinophils by IL-33, and investigated the underlying intracellular signaling mechanisms. IL-33 markedly enhanced eosinophil survival and upregulated cell surface expression of the adhesion molecule intercellular adhesion molecule (ICAM)-1 on eosinophils, but it suppressed that of ICAM-3 and L-selectin. In addition, IL-33 mediates significant release of the proinflammatory cytokine IL-6 and the chemokines CXCL8 and CCL2. We found that IL-33-mediated enhancement of survival, induction of adhesion molecules, and release of cytokines and chemokines were differentially regulated by activation of the nuclear factor (NF)-kB, p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathways. Furthermore, we compared the above IL-33 activities with two structurally and functionally related cytokines, IL-1b and IL-18. IL-1b, but not IL-18, markedly upregulated cell surface expression of ICAM-1. IL-1b and IL-18 also significantly enhanced eosinophil survival, and induced the release of IL-6 and chemokines CXCL8 and CCL2 via the activation of the NF-kB, p38 MAPK and ERK pathways. Synergistic effects on the release of IL-6 were also observed in combined treatment with IL-1b, IL-18 and IL-33. Taken together, our findings provide insight into IL-33-mediated activation of eosinophils via differential intracellular signaling cascades in the immunopathogenesis of allergic inflammation.

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Section: Introductionmentioning

confidence: 75%

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

et al. 2009

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“…PBTs were cultured with pyrrolidinedithiocarbamic acid (PDTC; 500 mM, 24 hours; Sigma), an inhibitor of NF-kB, to evaluate the role of NF-kB. 12 To evaluate pIkBa and GR nuclear translocation, PBTs were cultured (37°C, 5% CO 2 ) with FP, salmeterol, or both for 30 minutes.…”

Section: Pbt Culturesmentioning

confidence: 99%

“…12,19 The cytoplasmic and nuclear protein fractions were separated by using a commercial kit (Pierce, Rockford, Ill) to study GR nuclear translocation. Fifty micrograms of total protein was subjected to SDS-PAGE on 4% to 12% gradient gels (Novex, San Diego, Calif), blotted onto nitrocellulose membranes, blocked with PBS containing 3% BSA and 0.1% Tween 20, and then probed with a polyclonal antibody directed against human procaspases 3 and 8 (Pharmingen and Becton Dickinson), with a polyclonal antibody directed against human GRa (Santa Cruz Biotechnology, Santa Cruz, Calif) or with a polyclonal antibody recognizing pIkBa (Santa Cruz Biotechnology).…”

Section: Pbt Culturesmentioning

confidence: 99%

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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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“…Electrophoretic mobility-shift assays and immunohistochemical studies also suggest a greater activation of RelA-containing NF-B dimers in severe asthmatics (17). In mouse models of asthma, mice deficient in either the p50 (13,14) or the c-Rel (15) NF-B subunits, or mice treated with inhibitors of epithelial NF-B activity (18), have significantly reduced levels of eosinophilic lung inflammation when challenged with inhaled allergen.…”

mentioning

confidence: 98%

Allergen-induced peribronchial fibrosis and mucus production mediated by IκB kinase β-dependent genes in airway epithelium

Broide

Lawrence

Doherty

et al. 2005

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

140

127

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In response to inflammation or injury, airway epithelial cells express inducible genes that may contribute to allergen-induced airway remodeling. To determine the contribution of epithelial cell NF-B activation to the remodeling response, we generated CC10-Cre tg ͞Ikk␤ ⌬/⌬ mice in which NF-B signaling through I B kinase ␤ (IKK␤) is selectively ablated in the airway epithelium by conditional Cre-recombinase expression from the Clara cell (CC10) promoter. Repetitive ovalbumin challenge of mice deficient in airway epithelial IKK␤ prevented nuclear translocation of the RelA NF-B subunit only in airway epithelial cells, resulting in significantly lower peribronchial fibrosis in CC10-Cre tg ͞Ikk␤ ⌬/⌬ mice compared with littermate controls as assessed by peribronchial trichrome staining and total lung collagen content. Levels of airway mucus, airway eosinophils, and peribronchial CD4 ؉ cells in ovalbumin-challenged mice were also reduced significantly upon airway epithelial Ikk␤ ablation. The diminished inflammatory response was associated with reduced expression of NF-B-regulated chemokines, including eotaxin-1 and thymus-and activation-regulated chemokine, which attract eosinophils and Th2 cells, respectively, into the airway. The number of peribronchial cells expressing TGF-␤1, as well as TGF-␤1 amounts in bronchoalveolar lavage, were also significantly reduced in mice deficient in airway epithelium IKK␤. Overall, these studies show an important role for NF-B regulated genes in airway epithelium in allergen-induced airway remodeling, including peribronchial fibrosis and mucus production.asthma ͉ NF-B ͉ eosinophil ͉ TGF-␤

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Persistent Activation of Nuclear Factor–κB Signaling Pathway in Severe Uncontrolled Asthma

Cited by 163 publications

References 45 publications

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation

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

Allergen-induced peribronchial fibrosis and mucus production mediated by IκB kinase β-dependent genes in airway epithelium

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