FcεRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells Shigeru Okumura, DDS, PhD, Hironori Sagara,

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FcεRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells Shigeru Okumura, DDS, PhD, Hironori Sagara, MD, PhD, Takeshi Fukuda, MD, PhD, Hirohisa Saito, MD, PhD, Yoshimichi Okayama, MD, PhD Journal of Allergy and Clinical Immunology Volume 115, Issue 2, Pages 272-279 (February 2005) DOI: 10.1016/j.jaci.2004.10.004 Copyright © 2005 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 1 Representation of mRNA expression levels in control MCs, anti-IgE–stimulated MCs, and anti-IgE plus dexamethasone (DEX)–stimulated MCs. Human MCs were precultured with IgE in the presence or absence of dexamethasone and then activated with anti-IgE for 6 hours. Each row of colored bars represents 1 gene, and each column represents 1 stimulus. Colored bars show the magnitude of the response for each gene, according to the scale shown. I indicates a set of genes that were upregulated by anti-IgE stimulation but decreased by pretreatment with dexamethasone after activation with anti-IgE. II indicates a set of genes that were upregulated by anti-IgE-stimulation but not affected by dexamethasone pretreatment after activation with anti-IgE. III indicates a set of genes that were not affected by anti-IgE stimulation but were downregulated by dexamethasone treatment before activation with anti-IgE. IV indicates a set of genes were not affected by anti-IgE stimulation but were upregulated by dexamethasone pretreatment. Cont, Control. Journal of Allergy and Clinical Immunology 2005 115, 272-279DOI: (10.1016/j.jaci.2004.10.004) Copyright © 2005 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 2 Expression of amphiregulin (AREG) by human MCs. A, Upregulation of AREG expression in human MCs by FcεRI-mediated activation. Human MCs with (+) and without (−) pretreatment with dexamethasone (DEX) were cultured with IgE then activated with 1.5 μg/mL anti-IgE. Intracellular mRNA for AREG and GAPDH was amplified by RT-PCR. B, AREG secretion from MCs after anti-IgE (1.5 μg/mL) stimulation with (+) or without (−) dexamethasone pretreatment. Cell supernatants were harvested at 24 hours for ELISA of AREG (n=3 donors). C, Time course of AREG production by anti-IgE (1.5 μg/mL)-stimulated human MCs with (gray bar) or without (closed bars) dexamethasone pretreatment. Control cells were incubated with IgE in the presence (hatched bars) or absence (open bars) of dexamethasone, but anti-IgE was omitted. D, Concentration-response study of anti-IgE–induced AREG production by human MCs. MCs were preincubated with IgE and then activated with 0.1, 0.5, 1.5 or 5 μg/mL anti-IgE for 24 hours. ND, Not detected. Journal of Allergy and Clinical Immunology 2005 115, 272-279DOI: (10.1016/j.jaci.2004.10.004) Copyright © 2005 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 3 Effect of amphiregulin (AREG) on MUC2 and MUC5AC expression in NCI-H292 cells. NCI-H292 cells were incubated with 0.01 to 10 ng/mL rhAREG or 0.1 to 10 ng/mL rhEGF for 24 horus. Total RNA was extracted from the cells, and quantitative real-time RT-PCR analysis was used to determine the amounts of MUC2 (A) and MUC5AC (B) mRNA. The results were expressed as the fold change (mean ± SEM) in the mucin mRNA level of AREG-treated or EGF-treated cells compared with AREG-untreated or EGF-untreated cells (n=3). ∗P < .05 compared with cells not treated with AREG or EGF. Journal of Allergy and Clinical Immunology 2005 115, 272-279DOI: (10.1016/j.jaci.2004.10.004) Copyright © 2005 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 4 Activated MC supernatants increase MUC2 and MUC5AC gene expression mediated by amphiregulin (AREG). Confluent, serum-depleted NCI-H292 cells were pretreated with 1 μg/mL anti-AREG neutralizing antibody or 1 μg/mL mouse IgG1, and then incubated with unstimulated MC supernatant (Unsti MC SN) or activated MC supernatant (Stim MC SN) for 24 hours. Total RNA was extracted from the NCI-H292 cells, and quantitative real-time RT-PCR analysis was used to determine the amounts of MUC2 (A) and MUC5AC (B) mRNA. The results were expressed as the fold change (mean ± SEM) in the mucin mRNA level of anti-AREG mAb or mIgG1-treated cells incubated with activated MC supernatant compared with cells incubated with unstimulated MC supernatant (n=3). ∗P < .05, ∗∗P < .01 compared between cells treated with anti-AREG neutralizing antibody and treated with mIgG1. Journal of Allergy and Clinical Immunology 2005 115, 272-279DOI: (10.1016/j.jaci.2004.10.004) Copyright © 2005 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 5 Correlation of the number of amphiregulin (AREG)+ tryptase+ cells with the extent of goblet cell hyperplasia in the airways of asthmatic subjects. A, Colocalization of AREG in tryptase+ MCs. Two sequential 3-μm sections of bronchial biopsy specimens from subjects with asthma were immunostained for tryptase (left panel) and AREG (right panel). B, The number of AREG+ cells in 1 mm2 bronchial mucosa of normal control subjects (Control) and subjects with asthma (Asthma). AREG+ cells were counted in at least 6 high-power fields in each sample by three independent observers. ∗∗P < .01 compared between the number of AREG+ cells in control subjects and subjects with asthma. C, The number of AREG+tryptase+ cells in 1 mm2 bronchial mucosa of normal control subjects (Control) and subjects with asthma (Asthma). ∗∗P < .01 compared between the number of AREG+ tryptase+cells in control subjects and subjects with asthma. D, Percentages of AREG+ epithelial cells and eosinophils among total AREG+ cells in normal (open bar) and asthmatic lung (closed bar) samples. ∗P < .05 for the percentages of AREG+ epithelial cells in control subjects and subjects with asthma. E, Correlation of expression of AREG in MCs with the extent of goblet cell hyperplasia in patients with asthma. The extent of goblet cell hyperplasia was scored as described in the Methods section; its correlation with the number of AREG+tryptase+ cells in the airways of patients with asthma was analyzed. Journal of Allergy and Clinical Immunology 2005 115, 272-279DOI: (10.1016/j.jaci.2004.10.004) Copyright © 2005 American Academy of Allergy, Asthma and Immunology Terms and Conditions