Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease Tanya M. Laidlaw, MD, Anya J. Cutler, Molly S.

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Presentation transcript:

Prostaglandin E2 resistance in granulocytes from patients with aspirin-exacerbated respiratory disease Tanya M. Laidlaw, MD, Anya J. Cutler, Molly S. Kidder, Tao Liu, PhD, Juan Carlos Cardet, MD, Heng Chhay, Chunli Feng, MD, Joshua A. Boyce, MD Journal of Allergy and Clinical Immunology Volume 133, Issue 6, Pages 1692-1701.e3 (June 2014) DOI: 10.1016/j.jaci.2013.12.1034 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 LT production by fMLP-stimulated granulocytes and suppression by PGE2 and EP agonists. LTB4 (A) and cysLT (B) production by 0.5 × 106 granulocytes stimulated with 1 μM fMLP are shown from controls without asthma (white columns), controls with ATA (gray columns), and subjects with AERD (black columns). Percentage suppression of LTB4 (C) and cysLT (D) production by fMLP-stimulated granulocytes pretreated with the listed agonists is shown for cells from controls without asthma, controls with ATA, and subjects with AERD. Data are expressed as mean (±SEM) (*P < .05; **P < .01). Journal of Allergy and Clinical Immunology 2014 133, 1692-1701.e3DOI: (10.1016/j.jaci.2013.12.1034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Platelet-adherent neutrophils, LTB4 generation, and suppression of 5-LO activity in AERD. A, Percentages of platelet-adherent neutrophils in whole blood from 8 subjects with AERD are plotted against quantity of LTB4 generated by fMLP-stimulated granulocytes from the same individuals. Percentage suppression of fMLP-induced LTB4 by pretreatment with PGE2 (B) or the EP2 receptor-specific agonist (C) plotted against percentages of platelet-adherent neutrophils in the blood of each subject. Effect size (Pearson correlation) is denoted as an r value. Journal of Allergy and Clinical Immunology 2014 133, 1692-1701.e3DOI: (10.1016/j.jaci.2013.12.1034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 EP2 protein expression, cAMP accumulation, and inhibition of platelet CD62P. A, Representative flow cytometric histogram of intracellular EP2 is shown for neutrophils from a subject with AERD. Mean intracellular EP2 levels of neutrophils and eosinophils (B) and of platelets (D) are shown for controls without asthma (n = 6), controls with ATA (n = 5), and subjects with AERD (n = 16). Intracellular cAMP accumulation within granulocytes (C) or platelets (E) stimulated with listed agonists is shown. F, Inhibition of ADPβS-stimulated CD62P expression on platelets in platelet-rich plasma is shown. Data are expressed as mean (±SEM). There were no significant differences between patient groups for any comparisons in panels B-F. Journal of Allergy and Clinical Immunology 2014 133, 1692-1701.e3DOI: (10.1016/j.jaci.2013.12.1034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effect of H89 on LTB4 production from blood granulocytes. The effect of pretreatment of granulocytes with H89 on fMLP-induced LTB4 production is shown for controls without asthma (A) (n = 6), controls with ATA (B) (n = 6), and subjects with AERD (C) (n = 8). Data are expressed as mean (±SEM) (*P < .05; **P < .01). Journal of Allergy and Clinical Immunology 2014 133, 1692-1701.e3DOI: (10.1016/j.jaci.2013.12.1034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Granulocyte PKA activity and PKACγ subunit expression. A, Basal PKA activity measured by ELISA is shown. B, The net effect of H89 on granulocyte production of LTB4 is shown plotted again the basal PKA activity for each patient. Effect size is denoted as an r value. C, Representative Western blot of granulocytes for PKACγ protein, with GAPDH shown below. Of note, the 2 control subjects with ATA with the lowest PKACγ protein levels of that patient group are the 2 shown on this blot. D, Mean PKACγ protein levels normalized to GAPDH are shown. *P < .05. Journal of Allergy and Clinical Immunology 2014 133, 1692-1701.e3DOI: (10.1016/j.jaci.2013.12.1034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Specificity of EP2 antibody. A representative flow cytometric histogram of EP2-transfected human embryonic kidney 293 cells is shown, which demonstrates staining with the monoclonal antibody directed against the human EP2 receptor (black line) compared with staining with the isotype control (gray shading). Journal of Allergy and Clinical Immunology 2014 133, 1692-1701.e3DOI: (10.1016/j.jaci.2013.12.1034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Signaling mechanisms by which EP2, EP3, and EP4 receptors may control granulocyte PKA activity and LT production in controls (A) and patients with AERD (B). Journal of Allergy and Clinical Immunology 2014 133, 1692-1701.e3DOI: (10.1016/j.jaci.2013.12.1034) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions