Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor κB and c-Jun N-terminal kinase activation Alberto Papi, MD,

Slides:

Advertisements

Similar presentations

Proinflammatory cytokine–induced and chemical mediator–induced IL-8 expression in human bronchial epithelial cells through p38 mitogen-activated protein.

Advertisements

Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of.

Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD Rubaiyat Haque, MBBS,

Tissue factor–bearing exosome secretion from human mechanically stimulated bronchial epithelial cells in vitro and in vivo Jin-Ah Park, PhD, Asma S.

IL-13 and TH2 cytokine exposure triggers matrix metalloproteinase 7–mediated Fas ligand cleavage from bronchial epithelial cells Samuel J. Wadsworth,

Airway microbiome and responses to corticosteroids in corticosteroid-resistant asthma patients treated with acid suppression medications Elena Goleva,

TNF-α–mediated bronchial barrier disruption and regulation by src-family kinase activation Michelle A. Hardyman, PhD, Emily Wilkinson, BSc, Emma Martin,

Mechanism of glucocorticoid protection of airway smooth muscle from proasthmatic effects of long-acting β2-adrenoceptor agonist exposure Gustavo Nino,

Social stress and asthma: The role of corticosteroid insensitivity

Bruton tyrosine kinase mediates TLR9-dependent human dendritic cell activation Vassilios Lougaris, MD, Manuela Baronio, PhD, Massimiliano Vitali, PhD,

Nitric oxide inhibits human rhinovirus-induced transcriptional activation of CXCL10 in airway epithelial cells Rommy Koetzler, MD, MSc, Raza S. Zaheer,

Julie M. Caldwell, PhD, Carine Blanchard, PhD, Margaret H

Deficient glucocorticoid induction of anti-inflammatory genes in nasal polyp fibroblasts of asthmatic patients with and without aspirin intolerance Laura.

Peter J. Barnes, FMedSci, FRS

Differential control of TH1 versus TH2 cell responses by the combination of low-dose steroids with β2-adrenergic agonists Elena Goleva, PhD, Annegret.

Is 9 more than 2 also in allergic airway inflammation?

Specificity protein 1 is pivotal in the skin’s antiviral response

A role for phosphoinositol 3–kinase δ in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease John.

IL-10 inhibits CD28 and ICOS costimulations of T cells via src homology 2 domain— containing protein tyrosine phosphatase 1 Alison Taylor, PhD, Mübeccel.

The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells Jane Eddleston, PhD, Jack Herschbach,

The IL-17F signaling pathway is involved in the induction of IFN-γ–inducible protein 10 in bronchial epithelial cells Mio Kawaguchi, MD, Fumio Kokubu,

The innate antiviral response upregulates IL-13 receptor α2 in bronchial fibroblasts Gemma Campbell-Harding, PhD, Hannah Sawkins, BSc, Nicole Bedke, PhD,

Toluene downregulates filaggrin expression via the extracellular signal-regulated kinase and signal transducer and activator of transcription–dependent.

IL-13 desensitizes β2-adrenergic receptors in human airway epithelial cells through a 15-lipoxygenase/G protein receptor kinase 2 mechanism Giusy D.

Mechanisms of tissue inhibitor of metalloproteinase 1 augmentation by IL-13 on TGF- β1–stimulated primary human fibroblasts Xiuxia Zhou, PhD, Haizhen.

NEMO is a key component of NF-κB– and IRF-3–dependent TLR3-mediated immunity to herpes simplex virus Magali Audry, PhD, Michael Ciancanelli, PhD, Kun.

Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma Po-Jui Chang, MD, Pankaj K. Bhavsar, PhD,

Posttranscriptional regulation of IL-13 in T cells: Role of the RNA-binding protein HuR Vincenzo Casolaro, MD, PhD, Xi Fang, MD, Brian Tancowny, MS, Jinshui.

Steroid resistance of airway type 2 innate lymphoid cells from patients with severe asthma: The role of thymic stromal lymphopoietin Sucai Liu, PhD,

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M Qun Wu, MD, PhD, Di Jiang, BS, Sean Smith,

MicroRNA-9 regulates steroid-resistant airway hyperresponsiveness by reducing protein phosphatase 2A activity Jing Jing Li, MS, Hock L. Tay, PhD, Steven.

Inhibition of ABCC4 potentiates combination beta agonist and glucocorticoid responses in human airway epithelial cells Ryan D. Huff, MSc, Christopher.

Peter J. Barnes, FRS, FMedSci

Increased nuclear suppressor of cytokine signaling 1 in asthmatic bronchial epithelium suppresses rhinovirus induction of innate interferons Vera Gielen,

Loss of syk kinase during IgE-mediated stimulation of human basophils

Antiviral activity of human β-defensin 3 against vaccinia virus

Cold temperature induces mucin hypersecretion from normal human bronchial epithelial cells in vitro through a transient receptor potential melastatin.

Elucidating the effects of disease-causing mutations on STAT3 function in autosomal- dominant hyper-IgE syndrome Simon J. Pelham, MSc, Helen C. Lenthall,

Exogenous IFN-β has antiviral and anti-inflammatory properties in primary bronchial epithelial cells from asthmatic subjects exposed to rhinovirus Julie.

Nitric oxide inhibits IFN regulatory factor 1 and nuclear factor-κB pathways in rhinovirus- infected epithelial cells Rommy Koetzler, MD, MSc, Raza S.

Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of.

Cysteinyl leukotriene upregulates IL-11 expression in allergic airway disease of mice Kyung Sun Lee, PhD, So Ri Kim, MD, PhD, Hee Sun Park, MD, PhD, Seoung.

IκB kinase–driven nuclear factor-κB activation in patients with asthma and chronic obstructive pulmonary disease Rosalia Gagliardo, PhD, Pascal Chanez,

Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease Javier Milara, PhD, PharmD,

Connective tissue growth factor expression is regulated by histamine in lung fibroblasts: Potential role of histamine in airway remodeling Steffen Kunzmann,

Cockroach proteases increase IL-8 expression in human bronchial epithelial cells via activation of protease-activated receptor (PAR)–2 and extracellular-signal-regulated.

Expression of functional receptor activity modifying protein 1 by airway epithelial cells with dysregulation in asthma Kandace Bonner, BSc, Harsha H.

Volume 119, Issue 5, Pages (November 2000)

IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts Séverine Létuvé, PhD, Stéphane Lajoie-Kadoch, MSc, Séverine Audusseau,

Glucocorticoid-induced surface expression of annexin 1 blocks β2-integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate.

Ian Ashmole, PhD, S. Mark Duffy, PhD, Mark L. Leyland, PhD, Valerie S

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M Qun Wu, MD, PhD, Di Jiang, BS, Sean Smith,

P38 Mitogen-activated protein kinase–induced glucocorticoid receptor phosphorylation reduces its activity: Role in steroid-insensitive asthma Elvis Irusen,

Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: Involvement in patients with severe eosinophilic asthma

Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps Javier Milara, PhD, PharmD, Teresa Peiró,

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma Elisabetta Pace, MD, Rosalia Gagliardo,

Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling Richard Leigh, MBChB, PhD, Wale.

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Deficient antiviral immune responses in childhood: Distinct roles of atopy and asthma Simonetta Baraldo, PhD, Marco Contoli, MD, PhD, Erica Bazzan, PhD,

Heterozygous N-terminal deletion of IκBα results in functional nuclear factor κB haploinsufficiency, ectodermal dysplasia, and immune deficiency Douglas.

Zhenying Nie, PhD, Cole S. Nelson, PhD, David B. Jacoby, MD, Allison D

Steroids completely reverse albuterol-induced β2-adrenergic receptor tolerance in human small airways Philip R. Cooper, PhD, Reynold A. Panettieri, MD

Thymic stromal lymphopoietin is induced by respiratory syncytial virus–infected airway epithelial cells and promotes a type 2 response to infection Hai-Chon.

Nitrosative stress in the bronchial mucosa of severe chronic obstructive pulmonary disease Fabio L.M. Ricciardolo, MD, Gaetano Caramori, MD, PhD, Kazuhiro.

Salmeterol attenuates chemotactic responses in rhinovirus-induced exacerbation of allergic airways disease by modulating protein phosphatase 2A Luke.

Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma

Regulation of bronchial epithelial barrier integrity by type 2 cytokines and histone deacetylases in asthmatic patients Paulina Wawrzyniak, MSc, Marcin.

Transforming growth factor β1 increases fibronectin deposition through integrin receptor α5β1 on human airway smooth muscle Lyn M. Moir, PhD, Janette.

Natural history of cow’s milk allergy

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Presentation transcript:

Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor κB and c-Jun N-terminal kinase activation Alberto Papi, MD, Marco Contoli, MD, Ian M. Adcock, PhD, Cinzia Bellettato, PhD, Anna Padovani, BS, Paolo Casolari, PhD, Luminita A. Stanciu, PhD, Peter J. Barnes, MD, Sebastian L. Johnston, MD, Kazuhiro Ito, PhD, Gaetano Caramori, MD Journal of Allergy and Clinical Immunology Volume 132, Issue 5, Pages 1075-1085.e6 (November 2013) DOI: 10.1016/j.jaci.2013.05.028 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Rhinovirus infection induces dexamethasone insensitivity. A and C, IL-1β–induced CXCL8 production in A549 cells (Fig 1, A) and HBECs (Fig 1, C). B and D, Dexamethasone inhibition of IL-1β–induced CXCL8 production in A549 cells (Fig 1, B) and HBECs (Fig 1, D) in the presence (continuous line) or absence (dashed line) of rhinovirus infection. *P < .01 and #P < .05 for IC50 and Emax in infected versus uninfected cells, respectively. E and F, Dexamethasone-induced MKP-1 mRNA expression in A549 cells (Fig 1, E) and HBECs (Fig 1, F) in the presence or absence of RV-16 infection. G, Dexamethasone-induced GR-GRE binding in A549 cells. f-RV, Virus removed by means of filtration. Journal of Allergy and Clinical Immunology 2013 132, 1075-1085.e6DOI: (10.1016/j.jaci.2013.05.028) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Rhinovirus infection impairs dexamethasone-induced GRα nuclear translocation. A-D and G, Immunocytochemical evaluation of GRα nuclear translocation induced by dexamethasone (representative staining; Fig 2, A and B) in the presence or absence of RV-16 infection (Fig 2, C) at different time points after RV-16 (Fig 2, D) in A549 cells and primary epithelial cells (Fig 2, G). E and F, Results (means ± SEMs; Fig 2, F) and representative blots (Fig 2, E) of GRα Western blot analysis in nuclear extracts of A549 cells. Control refers to unstimulated and uninfected cells. f-RV, Virus removed by means of filtration. Journal of Allergy and Clinical Immunology 2013 132, 1075-1085.e6DOI: (10.1016/j.jaci.2013.05.028) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Rhinovirus-induced impairment of dexamethasone-induced GR nuclear translocation is partially NF-κB dependent. A and B, Immunocytochemical evaluation of nuclear p65 after RV-16 infection with or without IKK2 inhibitors (AS602868 [Fig 3, A] and PS1145 [Fig 3, B]) in A549 cells. C, Immunocytochemical evaluation of GRα nuclear translocation induced by dexamethasone in the presence of RV-16 with or without AS602868. D, Coimmunoprecipitation of GR associated to precipitated p65 in nuclear and cytoplasmic extracts of A549 cells. Lower films, Western blotting of immunoprecipitated p65 (IP: p65); upper films, Western blotting for GR bound to the immunoprecipitated p65 (WB: GR). The results of the graphs are expressed as the ratio between band density readings of GR and p65 (means ± SEMs). X, The ratio between GR and p65 was not calculated in the absence of RV-16–induced p65 nuclear translocation. **P < .01 versus all other conditions. f-RV, Virus removed by means of filtration. Journal of Allergy and Clinical Immunology 2013 132, 1075-1085.e6DOI: (10.1016/j.jaci.2013.05.028) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Rhinovirus-induced impairment of GR nuclear translocation is partially JNK dependent. A, Immunocytochemistry evaluation of phosphorylated JNK in A549 cells after RV-16 infection with or without pan-JNK inhibitor SP60012. B and C, Results (mean ± SEM; Fig 4, C) and representative blots (Fig 4, B) of GRα Western blot analysis in nuclear extracts of A549 induced by dexamethasone after RV-16 infection with or without JNK inhibitor SP60012. Control refers to unstimulated and uninfected cells. D and E, Results (means ± SEMs; Fig 4, E) and representative blots (Fig 4, D) of Western blot analysis of phosphorylated GR Ser226/GRα ratio in whole-cell lysates of A549 after RV-16 infection with or without the JNK inhibitor SP60012 or the IKK2 inhibitor PS1145. F, GR-GRE binding in nuclear extracts of A549 cells stimulated with dexamethasone after RV-16 infection without (Scramble) or with JNK-1 or JNK-2 siRNA. f-RV, Virus removed by means of filtration. Journal of Allergy and Clinical Immunology 2013 132, 1075-1085.e6DOI: (10.1016/j.jaci.2013.05.028) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Rhinovirus-induced attenuation of dexamethasone activity is reversed by a combination of JNK and IKK2 inhibitors. A, GR-GRE binding in nuclear extracts of A549 cells stimulated with dexamethasone after prior infection of cells with RV-16 in the presence (+) or absence of the JNK inhibitor SP600125 and the IKK2 inhibitor PS1145. B, Dexamethasone-induced MKP-1 mRNA expression after 4 hours in A549 cells after prior infection of cells with RV-16 in the presence (+) or absence of SP600125 and PS1145. C, Ability of dexamethasone to inhibit IL-1β–induced CXCL8 production, which is inhibited by RV-16 pretreatment, is restored by the combination of SP600125 and PS1145. Journal of Allergy and Clinical Immunology 2013 132, 1075-1085.e6DOI: (10.1016/j.jaci.2013.05.028) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 RV-1B infection induces glucocorticoid insensitivity and impairs GRα nuclear translocation. A, Dexamethasone inhibition of IL-1β–induced CXCL8 production in A549 cells in the presence (continuous line) or absence (dashed line) of RV-1B. *P < .01. B, Dexamethasone-induced MKP-1 mRNA expression in A549 cells in the presence (+) or absence (−) of RV-1B. In selected experiments cells were exposed to medium in which virus was removed by means of filtration (f-RV). ***P < .001 versus control (untreated and unexposed cells). ∧P < .05 versus dexamethasone-treated cells. C, RV-1B infection led to titer-dependent inhibition of dexamethasone-induced GR nuclear translocation in primary bronchial epithelial cells (P < .001, ANOVA). ∧∧∧P < .001 versus untreated and uninfected cells. ***P < .001 versus dexamethasone-treated uninfected cells. **P < .01 versus dexamethasone-treated uninfected cells. *P < .01. Journal of Allergy and Clinical Immunology 2013 132, 1075-1085.e6DOI: (10.1016/j.jaci.2013.05.028) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Western blot analysis of p65 in the cytoplasmic compartment of A549 cells after RV-16 infection. Western blot analysis of NF-κB p65 in cytoplasmic extracts of A549 cells exposed to RV-16 infection for 1 hour. A representative blot of 3 independent experiments is shown in the upper panel. A graphic representation of the densitometric data defined as means ± SEMs is shown in the lower panel. *P < .01. Journal of Allergy and Clinical Immunology 2013 132, 1075-1085.e6DOI: (10.1016/j.jaci.2013.05.028) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 RV-16–induced impairment of GR nuclear translocation is NF-κB dependent. A549 cells positive for nuclear GRα by means of immunocytochemical staining after exposure to dexamethasone plus RV-16 alone or RV-16 in the presence of the IKK2 inhibitor PS1145. ***P < .001 versus untreated cells. ∧∧P < .01 versus dexamethasone-treated cells. ∧P < .05 versus dexamethasone-treated cells. °P < .05 versus dexamethasone-treated and infected cells. Journal of Allergy and Clinical Immunology 2013 132, 1075-1085.e6DOI: (10.1016/j.jaci.2013.05.028) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions