Airway epithelial cells activate TH2 cytokine production in mast cells through IL-1 and thymic stromal lymphopoietin Deepti R. Nagarkar, PhD, Julie A.

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Presentation transcript:

Airway epithelial cells activate TH2 cytokine production in mast cells through IL-1 and thymic stromal lymphopoietin Deepti R. Nagarkar, PhD, Julie A. Poposki, MS, Michael R. Comeau, BSc, Assel Biyasheva, PhD, Pedro C. Avila, MD, Robert P. Schleimer, PhD, Atsushi Kato, PhD Journal of Allergy and Clinical Immunology Volume 130, Issue 1, Pages 225-232.e4 (July 2012) DOI: 10.1016/j.jaci.2012.04.019 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IL-4 plus dsRNA–stimulated NHBE cells promote TH2 cytokine production in mast cells. NHBE cells were stimulated with 100 ng/mL TNF, 100 ng/mL IL-4, 10 ng/mL IFN-γ, and 100 ng/mL IL-17A alone or in combination with 5 μg/mL dsRNA for 72 hours. Mast cells were then stimulated with derived supernatants (20% volume) for 48 hours (A and B). Mast cells were stimulated directly with IL-4 and dsRNA or with NHBE supernatants (NHBE Sup; C). IL-5 (Fig 1, A and C) and IL-13 (Fig 1, B) production was assessed by using the cytometric bead array. Results shown are means ± SEMs of 9 (Fig 1, A and B) or 3 to 5 (Fig 1, C) independent experiments with 3 NHBE cell donors and 3 mast cell donors. *P < .05 compared with all other groups, 1-way ANOVA. Journal of Allergy and Clinical Immunology 2012 130, 225-232.e4DOI: (10.1016/j.jaci.2012.04.019) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Neutralization of IL-1 and TSLP suppresses NHBE cell supernatant–induced IL-5 production in mast cells. Mast cells were stimulated with 10 ng/mL IL-1α, 10 ng/mL IL-1β, and 10 ng/mL TSLP; epithelial culture medium (bronchial epithelial cell growth medium [BEGM], 10% volume); or IL-4 plus dsRNA–stimulated NHBE cell supernatants (NHBE Sup; 10% volume) for 48 hours along with neutralizing antibodies against IL-1α (10 μg/mL, A), IL-1β (10 μg/mL, B), TSLP (32 μg/mL, C), or respective isotype controls. IL-5 responses were measured by using the cytometric bead array. Results shown are means ± SEMs of 7 (Fig 2, A), 6 (Fig 2, B), or 4 (Fig 2, C) independent experiments with 2 NHBE cell donors and 6 mast cell donors. *P < .05, paired Student t test. Journal of Allergy and Clinical Immunology 2012 130, 225-232.e4DOI: (10.1016/j.jaci.2012.04.019) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Induction of cytokines after NHBE cell stimulation. NHBE cells were stimulated with 100 ng/mL IL-4, 10 ng/mL IFN-γ, 100 ng/mL IL-17A, and 100 ng/mL TNF alone or in combination with 5 μg/mL dsRNA for 72 hours. Concentrations of cytokines were measured by using the cytometric bead array (IL-1α [A] and IL-1β [B]) or ELISA (IL-1Ra [C] and TSLP [D]). Results shown are means ± SEMs of 8 (Fig 3, A and B), 9 (Fig 3, C), and 6 (Fig 3, D) independent experiments with 5 NHBE cell donors. *P < .05, different from medium; †P < .05, different from dsRNA, 1-way ANOVA Journal of Allergy and Clinical Immunology 2012 130, 225-232.e4DOI: (10.1016/j.jaci.2012.04.019) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Correlation of cytokines TSLP (A) IL-1a (B), IL-1b (C), and the ratio of IL-1Ra (D) and IL-1/ IL-1Ra (E and F) in supernatants from IL-4 plus dsRNA–stimulated NHBE cells with IL-5 production in mast cells. Data are representative of 2 mast cell donors and 3 NHBE cell donors (n = 5). The correlations were assessed by using the Spearman rank correlation. NS, Not significant. Journal of Allergy and Clinical Immunology 2012 130, 225-232.e4DOI: (10.1016/j.jaci.2012.04.019) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IL-4 and dsRNA dose-dependently and synergistically enhance IL-5 production in mast cells when cocultured with epithelial cells. Mast cells were overlayed on NHBE cells and then stimulated with 10 ng/mL IL-4 and 5 μg/mL dsRNA (A) or at indicated concentrations (B) for 72 hours. Production of IL-5 was measured by using the cytometric bead array. Results shown are means ± SEMs of 6 independent experiments with 4 NHBE cell donors and 3 mast cell donors. *P < .05, 1-way ANOVA (Fig 5, A) and different from all groups; †different from medium, 0.1, 1, and 100 ng/mL IL-4; **P < .05, compared with medium and 0.1 ng/mL IL-4; ¶P < .05, compared with medium and 1 ng/mL IL-4, repeated-measures 1-way ANOVA Newman-Keuls test (Fig 5, B). Journal of Allergy and Clinical Immunology 2012 130, 225-232.e4DOI: (10.1016/j.jaci.2012.04.019) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 IL-4 and dsRNA enhance IL-5 production in mast cells when cocultured with NHBE cells in an IL-1– and TSLP-dependent manner. Mast cells were overlayed on NHBE cells and then stimulated with 10 ng/mL IL-4 and 5 μg/ml dsRNA, along with neutralizing antibodies against IL-1α, IL-1β, IL-1Ra (all from A), TSLP (B), or isotype controls for 72 hours. IL-5 response was measured by using the cytometric bead array. Results shown are means ± SEMs of 5 (Fig 6, A) or 4 (Fig 6, B) independent experiments with 2 NHBE cell donors and 3 mast cell donors. *P < .05, paired Student t test. Journal of Allergy and Clinical Immunology 2012 130, 225-232.e4DOI: (10.1016/j.jaci.2012.04.019) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 The combination of IL-4 and IV enhances IL-5 production from mast cells cocultured with NHBE cells. NHBE cells were stimulated with IV at an MOI of 0.1 and 10 ng/mL IL-4 along with neutralizing antibody to IL-1Ra at 20 μg/mL or with 20 μg/mL control goat IgG for 72 hours. Results shown are means ± SEMs of 5 independent experiments with 4 NHBE cell donors and 3 mast cell donors. *P < .05, 1-way ANOVA. Journal of Allergy and Clinical Immunology 2012 130, 225-232.e4DOI: (10.1016/j.jaci.2012.04.019) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Effect of IL-4 plus dsRNA–stimulated NHBE cells on mast cell degranulation. Mast cells were incubated with NHBE cell supernatants (NHBE Sup; 10% volume) or 1 μmol/L calcium ionophore A23187 (positive control) for 30 minutes. Cells were centrifuged, and supernatants were incubated with p-nitrophenyl-acetyl-d-glucosamine substrate for 90 minutes. Absorbances were read at 405 and 630 nm, and the percentage of net specific release was calculated. Results shown are means ± SEMs of 3 independent experiments. *P < .05. Journal of Allergy and Clinical Immunology 2012 130, 225-232.e4DOI: (10.1016/j.jaci.2012.04.019) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Neutralization of IL-1 suppresses NHBE cell supernatant–induced IL-5 production in mast cells. Mast cells were stimulated with 10 ng/mL IL-1α, 10 ng/mL IL-1β, and 10 ng/ml TSLP; epithelial culture medium (bronchial epithelial cell growth medium [BEGM], 10% volume); or IL-4 plus dsRNA–stimulated NHBE supernatants (NHBE Sup; 10% volume) for 48 hours along with neutralizing antibodies against IL-1α (10 μg/mL, A), IL-1β (10 μg/mL, B), or respective isotype controls. IL-5 responses were measured by using the cytometric bead array. Results shown are means ± SEMs of 5 independent experiments. *P < .05, paired Student t test. Journal of Allergy and Clinical Immunology 2012 130, 225-232.e4DOI: (10.1016/j.jaci.2012.04.019) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Induction of IL-1Ra by IV infection. NHBE cells cocultured with mast cells were stimulated with IV at an MOI of 0.1 and 10 ng/mL IL-4 for 72 hours. Concentrations of IL-1Ra were measured by using ELISA. Results shown are means ± SEMs of 6 independent experiments with 4 NHBE cell donors and 3 mast cell donors. *P < .05, 1-way ANOVA. Journal of Allergy and Clinical Immunology 2012 130, 225-232.e4DOI: (10.1016/j.jaci.2012.04.019) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions