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

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Presentation on theme: "Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor κB and c-Jun N-terminal kinase activation  Alberto Papi, MD,"— Presentation transcript:

1 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 e6 (November 2013) DOI: /j.jaci Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 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  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 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  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 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 (AS [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 AS 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  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 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 SP 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 SP 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  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 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 SP 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 SP 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 SP and PS1145. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 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  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 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  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 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  , e6DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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