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

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The innate antiviral response upregulates IL-13 receptor α2 in bronchial fibroblasts Gemma Campbell-Harding, PhD, Hannah Sawkins, BSc, Nicole Bedke, PhD, Stephen T. Holgate, DM, Donna E. Davies, PhD, Allison- Lynn Andrews, PhD Journal of Allergy and Clinical Immunology Volume 131, Issue 3, Pages 849-855.e5 (March 2013) DOI: 10.1016/j.jaci.2012.08.030 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IL-13Rα2 is upregulated by IFN-β. Fibroblasts from 5 healthy donors (open symbols) and 6 asthmatic donors (solid symbols) were grown to confluence and serum starved before treatment with IFN-β (10-100 IU), IFN-γ (10 ng/mL), or serum-free medium alone for 24 hours. Cells were analyzed for IL-13Rα2 surface expression by using flow cytometry. Data were normalized and expressed as specific mean fluorescence intensity (SMFI). ***P < .001 versus untreated control. Journal of Allergy and Clinical Immunology 2013 131, 849-855.e5DOI: (10.1016/j.jaci.2012.08.030) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Poly (I:C) induces IL-13Rα2 expression by means of de novo protein synthesis. Fibroblasts from 4 healthy donors were serum starved before treatment in the absence or presence of cycloheximide (CHX; 50 μg/mL) with control medium alone (C), 10 μg/mL Poly (I:C) or 100 IU of IFN-β for 24 hours. Expression of IL-13Rα2 mRNA was measured by using real-time quantitative PCR (A), and cell-surface expression of IL-13Ra2 was analyzed by using flow cytometry (B). Data were normalized to the average Δ cycle threshold (Fig 2, A) or the specific mean fluorescence intensity (Fig 2, B) of IL-13Rα2 in the unstimulated controls. *P < .05, **P < .01, and ***P < .001 versus untreated controls. Journal of Allergy and Clinical Immunology 2013 131, 849-855.e5DOI: (10.1016/j.jaci.2012.08.030) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Upregulation of IL-13Rα2 by Poly (I:C) is mediated by IFN-β. Fibroblasts (n = 4 healthy donors) were incubated in the absence or presence of an IFN-α/β receptor neutralizing antibody (IFN-α/β R NAb) or isotype control before treatment with control medium alone (C) or with Poly (I:C) (10 μg/mL) for 24 hours. Cell-surface expression of IL-13Rα2 was analyzed by using fluorescence-activated cell sorting. ***P < .001. Ab, Antibody. Journal of Allergy and Clinical Immunology 2013 131, 849-855.e5DOI: (10.1016/j.jaci.2012.08.030) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Pretreatment with Poly (I:C) attenuates IL-13–mediated eotaxin production. Fibroblasts from 3 healthy and 3 asthmatic donors were treated in the absence or presence of Poly (I:C) (10 μg/mL) for 24 hours. The cells were then challenged with IL-13 (10 ng/mL) for 24 hours. An IL-13Rα2 neutralizing antibody (NAb; 1 μg/mL) was included where indicated. Eotaxin was measured by using ELISA. ***P < .01. Journal of Allergy and Clinical Immunology 2013 131, 849-855.e5DOI: (10.1016/j.jaci.2012.08.030) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Upregulation of IL-13Rα2 is attenuated by dexamethasone (Dex). Fibroblasts from 4 healthy and 5 asthmatic donors were serum starved and treated with control medium alone (C), Poly (I:C) (10 μg/mL) or IFN-β (50 IU) in the absence or presence of 50 nmol/L dexamethasone for a further 24 hours. Surface expression of IL-13Rα2 was analyzed by using flow cytometry. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2013 131, 849-855.e5DOI: (10.1016/j.jaci.2012.08.030) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Proposed mechanism for the role of IL-13Rα2 in the epithelial-mesenchymal trophic unit (EMTU). Epithelial cells from asthmatic donors produce less IFN-β in response to rhinovirus infection, which might be insufficient to increase IL-13Rα2 expression in fibroblasts. Consequently, in asthmatic patients fibroblasts are unable to attenuate IL-13–mediated responses, such as eotaxin production. Because eotaxin is a powerful eosinophilic chemoattractant, this might partially explain the persistent eosinophilia observed in asthmatic patients during viral infections. Journal of Allergy and Clinical Immunology 2013 131, 849-855.e5DOI: (10.1016/j.jaci.2012.08.030) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Optimization of IL-13Rα2 flow cytometry. Fibroblasts were detached from culture by using trypsin or cell-dissociation solution. Cells were analyzed for cell-surface expression of IL-13Rα2 by using fluorescence-activated cell sorting. No difference was observed in baseline expression of IL-13Rα2. Journal of Allergy and Clinical Immunology 2013 131, 849-855.e5DOI: (10.1016/j.jaci.2012.08.030) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Poly (I:C) induces IFN-β and IL-13Rα2 mRNA. Fibroblasts from healthy (n = 11, open symbols) or asthmatic (n = 10, solid symbols) donors were serum starved before treatment with 0 to 10 μg/mL Poly (I:C) for 24 hours (A) or 10 μg/mL Poly (I:C) for the times indicated (B). Expression of IFN-β–induced IL-13Rα2 mRNA was measured by using real-time quantitative PCR. Data have been normalized to the average Δ cycle threshold of the unstimulated controls. **P < .01 and ***P < .001 versus untreated controls. Journal of Allergy and Clinical Immunology 2013 131, 849-855.e5DOI: (10.1016/j.jaci.2012.08.030) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Pretreatment with Poly (I:C) attenuates IL-13–mediated IL-6 production. Fibroblasts from 3 healthy and 3 asthmatic donors were treated in the absence or presence of Poly (I:C) (10 μg/mL) for 24 hours. The cells were then challenged with IL-13 (10 ng/mL) for 24 hours. An IL-13Rα2 neutralizing antibody (NAb; 1 μg/mL) was included where indicated. IL-6 levels were measured by using ELISA. ***P < .01. Journal of Allergy and Clinical Immunology 2013 131, 849-855.e5DOI: (10.1016/j.jaci.2012.08.030) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions