Low E-prostanoid 2 receptor levels and deficient induction of the IL-1β/IL-1 type I receptor/COX-2 pathway: Vicious circle in patients with aspirin-exacerbated.

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Low E-prostanoid 2 receptor levels and deficient induction of the IL-1β/IL-1 type I receptor/COX-2 pathway: Vicious circle in patients with aspirin-exacerbated respiratory disease Liliana Machado-Carvalho, MS, Margarita Martín, PhD, Rosa Torres, PhD, Marta Gabasa, PhD, Isam Alobid, MD, PhD, Joaquim Mullol, MD, PhD, Laura Pujols, PhD, Jordi Roca-Ferrer, PhD, Cesar Picado, MD, FERS, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 1, Pages 99-107.e7 (January 2016) DOI: 10.1016/j.jaci.2015.09.028 Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Basal and IL-1β–induced expression of IL-1RI in NM-C and NP-AERD fibroblasts. NM-C and NP-AERD fibroblasts (n = 8) were incubated with SFM for 24 hours and with or without IL-1β (10 ng/mL) for an additional 24 hours. IL-1RI levels were measured by means of Western blotting and quantitative real-time PCR. A and C, Densitometric analysis and representative Western blotting of IL-1RI protein expression normalized to β-actin. B and D, IL-1RI mRNA expression was analyzed by means of quantitative real-time PCR and normalized to GAPDH. *P < .05 and **P < .01 compared with respective untreated cells, ##P < .01 and ###P < .001 compared with NM-C fibroblasts under the same conditions. Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Basal and IL-1β–induced expression of COX-2 in cultured NM-C and NP-AERD fibroblasts. NM-C and NP-AERD fibroblasts (n = 8) were incubated with or without IL-1β (10 ng/mL for 24 hours), and COX-2 levels were measured by means of Western blotting and quantitative real-time PCR. A, Densitometric analysis and representative Western blotting of COX-2 protein expression normalized to β-actin. B, COX-2 mRNA expression was analyzed by means of quantitative real-time PCR and normalized to GAPDH. *P < .05 and **P < .01 compared with respective untreated cells, #P < .05 and ###P < .001 compared with NM-C fibroblasts under the same conditions. Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Basal and IL-1β–induced expression of mPGES-1 in cultured NM-C and NP-AERD fibroblasts. NM-C and NP-AERD fibroblasts (n = 8) were incubated with or without IL-1β (10 ng/mL for 24 hours), and mPGES-1 levels were measured by means of Western blotting. Densitometric analysis and representative Western blotting of mPGES-1 protein expression normalized to β-actin. *P < .05 and **P < .01 compared with respective untreated cells. ###P < .001 compared with NM-C fibroblasts under the same conditions. Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Correlations between IL-1β–induced expression of IL-1RI and IL-1β–induced expression of COX-2 and mPGES-1 in cultured NM-C and NP-AERD fibroblasts. The fitting line equation, Pearson correlation coefficient, and associated P value are shown at the upper region of the graph. A and B, Correlation between IL-1β–induced expression of IL-1RI and IL-1β–induced expression of COX-2 (Fig 4, A) and mPGES-1 (Fig 4, B). White circles, NM-C fibroblasts (n = 8); black diamonds, NP-AERD fibroblasts (n = 8). C, Effect of IL-1RI gene silencing by means of siRNA on COX-2 and mPGES-1 expression in cultured NM-C fibroblasts (n = 8). Representative Western blotting of IL-1RI, COX-2, and mPGES-1 expression normalized to β-actin after cell stimulation with IL-1β (10 ng/mL for 24 hours). Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Effect of exogenous PGE2 on IL-1RI expression in cultured NM-C and NP-AERD fibroblasts. Densitometric analysis and representative Western blotting of IL-1RI expression normalized to β-actin after cell stimulation with PGE2 (10−7 to 10−5 mol/L) for 24 hours (n = 8; A) and IL-1RI expression normalized to β-actin after cell stimulation with or without IL-1β (10 ng/mL) for 24 hours (n = 8; B) in the presence or absence of ASA (10−5 and 10−3 mol/L). *P < .05 and **P < .01 compared with respective untreated cells. #P < .05, ##P < .01, and ###P < .001 compared with NM-C fibroblasts under the same conditions. †P < .05 compared with respective cells treated with IL-1β (10 ng/mL). Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Effect of EP2 and EP4 receptor agonists on IL-1RI expression in cultured NM-C and NP-AERD fibroblasts. Densitometric analysis and representative Western blotting of IL-1RI expression normalized to β-actin after cell stimulation with or without butaprost (10−7 to 10−5 mol/L; A) or CAY10598 (10−7 to 10−5 mol/L) for 24 hours (n = 8; B). *P < .05 and **P < .01 compared with respective untreated cells. #P < .05, ##P < .01, and ###P < .001 compared with NM-C fibroblasts under the same conditions. Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Effect of transient transfection of EP2 receptor on PGE2-induced IL-1RI expression and IL-1β–induced COX-2 and mPGES-1 expression in cultured NP-AERD fibroblasts. Cells (n = 8) were transiently transfected with expression plasmids encoding GFP chimeras of EP2 receptor by using Lipofectamine 2000 reagent and incubated with or without PGE2 (10−7 to 10−5 mol/L) or with or without IL-1β (10 ng/mL) for 24 hours. Results of densitometric analysis and representative Western blotting of IL-1RI (A), COX-2 (B), and mPGES-1 (C) expression normalized to β-actin in nontransfected NM-C fibroblasts and transfected NP-AERD fibroblasts are shown. Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 Schematic representation of the proposed mechanisms underlying regulation of IL-1RI. IL-1β binds with high affinity to IL-1RI and stimulates both COX-2 and mPGES-1 expression, increasing the production and secretion of PGE2. PGE2 (or selective EP2 receptor agonists) activates EP2 receptors and induces the increase of the secondary messenger cAMP, which is also stimulated by forskolin. The increase in cAMP production activates PKA, which stimulates IL-1RI expression, thereby indicating a potential positive feedback mechanism for this pathway. Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Immunofluorescence of IL-1RI in cultured NM-C and NP-AERD fibroblasts. Cells (n = 8) were incubated with media (A and C) or 10 ng/mL IL-1β (B and D) for 24 hours, and immunofluorescence staining of IL-1RI (red) was performed. Nuclei (blue) were stained with 4′-6-diamidino-2-phenylindole dihydrochloride (×20 magnification). Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Basal expression of EP receptors in cultured NM-C and NP-AERD fibroblasts. Results of densitometric analysis and representative Western blotting of EP2 (A), EP3 (B), and EP4 (C) receptor expression normalized to β-actin (n = 8) are shown. ##P < .01 and ###P < .001 compared with NM-C fibroblasts under the same conditions. Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Effect of forskolin on IL-1RI expression in cultured NM-C and NP-AERD fibroblasts. Results of densitometric analysis and representative Western blotting of IL-1RI expression normalized to β-actin in cells treated with or without forskolin (20 μmol/L) for 24 hours (n = 8) are shown. *P < .05 compared with respective untreated cells. ###P < .001 compared with NM-C fibroblasts under the same conditions. Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Transient transfection of EP2 receptor in cultured NP-AERD fibroblasts. Cells (n = 8) were transiently transfected with expression plasmids encoding GFP as control or with GFP chimeras of EP2 receptor. A, Representative fluorescence images of GFP plasmid (1), EP2-GFP plasmid (2), and a negative control (3) taken 24 hours after transfection with an Axiovert 200M (Zeiss) inverted fluorescence microscope (×40 magnification). B, Representative blots of EP2, GFP, and β-actin expression. Journal of Allergy and Clinical Immunology 2016 137, 99-107.e7DOI: (10.1016/j.jaci.2015.09.028) Copyright © 2015 American Academy of Allergy, Asthma & Immunology Terms and Conditions