Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric.

Slides:

Advertisements

Similar presentations

Anju T. Peters, MD, Atsushi Kato, PhD, Ning Zhang, PhD, David B

Advertisements

Forkhead box protein 3 in human nasal polyp regulatory T cells is regulated by the protein suppressor of cytokine signaling 3 Feng Lan, MD, Nan Zhang,

Russell S. Traister, MD, PhD, Crystal E. Uvalle, BS, Gregory A

Forkhead box protein 3 in human nasal polyp regulatory T cells is regulated by the protein suppressor of cytokine signaling 3 Feng Lan, MD, Nan Zhang,

Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric.

The antimicrobial protein short palate, lung, and nasal epithelium clone 1 (SPLUNC1) is differentially modulated in eosinophilic and noneosinophilic chronic.

Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic.

Heterogeneous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois Bruce K. Tan, MD, MS, Aiko I. Klingler, PhD,

Proprotein convertases generate a highly functional heterodimeric form of thymic stromal lymphopoietin in humans Julie A. Poposki, MS, Aiko I. Klingler,

Evidence for intranasal antinuclear autoantibodies in patients with chronic rhinosinusitis with nasal polyps Bruce K. Tan, MD, Quan-Zhen Li, PhD, Lydia.

IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis Hyun-Woo Shin, MD, PhD, Dong-Kyu Kim, MD, Min-Hyun Park, MD,

Anju T. Peters, MD, Atsushi Kato, PhD, Ning Zhang, PhD, David B

IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: Implications for chronic obstructive pulmonary disease

Julie M. Caldwell, PhD, Carine Blanchard, PhD, Margaret H

IL-4 confers resistance to IL-27–mediated suppression on CD4+ T cells by impairing signal transducer and activator of transcription 1 signaling Zhihong.

Cell-specific activation profile of extracellular signal-regulated kinase 1/2, Jun N-terminal kinase, and p38 mitogen-activated protein kinases in asthmatic.

Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin Mohan S. Maddur, DVM, Janakiraman Vani,

Estrogen and progesterone decrease let-7f microRNA expression and increase IL-23/IL- 23 receptor signaling and IL-17A production in patients with severe.

Specificity protein 1 is pivotal in the skin’s antiviral response

Expression of 11β-hydroxysteroid dehydrogenase 1 and 2 in patients with chronic rhinosinusitis and their possible contribution to local glucocorticoid.

Evidence of a role for B cell–activating factor of the TNF family in the pathogenesis of chronic rhinosinusitis with nasal polyps Atsushi Kato, PhD,

The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells Jane Eddleston, PhD, Jack Herschbach,

Oncostatin M promotes mucosal epithelial barrier dysfunction, and its expression is increased in patients with eosinophilic mucosal disease Kathryn L.

Role of TWIK-related potassium channel-1 in chronic rhinosinusitis

Evidence for altered levels of IgD in the nasal airway mucosa of patients with chronic rhinosinusitis Jin-Young Min, MD, PhD, Jayakar V. Nayak, MD, PhD,

Neutrophils are a major source of the epithelial barrier disrupting cytokine oncostatin M in patients with mucosal airways disease Kathryn L. Pothoven,

Toll-like receptor 9 suppression in plasmacytoid dendritic cells after IgE-dependent activation is mediated by autocrine TNF-α John T. Schroeder, PhD,

The IL-17F signaling pathway is involved in the induction of IFN-γ–inducible protein 10 in bronchial epithelial cells Mio Kawaguchi, MD, Fumio Kokubu,

Reply The Journal of Allergy and Clinical Immunology: In Practice

IL-13 desensitizes β2-adrenergic receptors in human airway epithelial cells through a 15-lipoxygenase/G protein receptor kinase 2 mechanism Giusy D.

Increased expression of CC chemokine ligand 18 in patients with chronic rhinosinusitis with nasal polyps Sarah Peterson, MD, Julie A. Poposki, MS, Deepti.

Griet A. Van Roey, PhD, Christopher C

Miriam Wittmann, MD, Jana Zeitvogel, Dong Wang, MD, Thomas Werfel, MD

Culture medium from TNF-α–stimulated mesenchymal stem cells attenuates allergic conjunctivitis through multiple antiallergic mechanisms Wenru Su, MD,

Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma Po-Jui Chang, MD, Pankaj K. Bhavsar, PhD,

Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages Elena Goleva, PhD, Pia J. Hauk, MD, Clifton.

Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: Important implications in asthma Fei Huang, PhD, Shinichiro Wachi, PhD,

Cigarette smoke combined with Toll-like receptor 3 signaling triggers exaggerated epithelial regulated upon activation, normal T-cell expressed and secreted/CCL5.

David D. Tieu, MD, Anju T. Peters, MD, Roderick T

Superior anti-inflammatory effects of narrow-spectrum kinase inhibitors in airway smooth muscle cells from subjects with chronic obstructive pulmonary.

Cold temperature induces mucin hypersecretion from normal human bronchial epithelial cells in vitro through a transient receptor potential melastatin.

Microparticles in nasal lavage fluids in chronic rhinosinusitis: Potential biomarkers for diagnosis of aspirin-exacerbated respiratory disease Toru Takahashi,

Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis Deepti R. Nagarkar, PhD, Julie A. Poposki,

Increased expression of the epithelial anion transporter pendrin/SLC26A4 in nasal polyps of patients with chronic rhinosinusitis Sudarshan Seshadri,

Nitric oxide inhibits IFN regulatory factor 1 and nuclear factor-κB pathways in rhinovirus- infected epithelial cells Rommy Koetzler, MD, MSc, Raza S.

Sudarshan Seshadri, PhD, Mariel Rosati, BS, David C

Chronic rhinosinusitis with nasal polyps is characterized by B-cell inflammation and EBV-induced protein 2 expression Kathryn E. Hulse, PhD, James E.

Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1) Kornvalee Meesilpavikkai,

Cysteinyl leukotriene upregulates IL-11 expression in allergic airway disease of mice Kyung Sun Lee, PhD, So Ri Kim, MD, PhD, Hee Sun Park, MD, PhD, Seoung.

Increased noneosinophilic nasal polyps in chronic rhinosinusitis in US second- generation Asians suggest genetic regulation of eosinophilia Mahboobeh.

Staphylococcal exotoxins are strong inducers of IL-22: A potential role in atopic dermatitis Margarete Niebuhr, MD, Helena Scharonow, MS, Merle Gathmann,

Glandular mast cells with distinct phenotype are highly elevated in chronic rhinosinusitis with nasal polyps Tetsuji Takabayashi, MD, Atsushi Kato, PhD,

Josée Lamoureux, PhD, Jana Stankova, PhD, Marek Rola-Pleszczynski, MD

3-O-Formyl-20R,21-epoxyresibufogenin suppresses IL-6–type cytokine actions by targeting the glycoprotein 130 subunit: Potential clinical implications

IL-25 as a novel therapeutic target in nasal polyps of patients with chronic rhinosinusitis Hyun-Woo Shin, MD, PhD, Dong-Kyu Kim, MD, Min-Hyun Park, MD,

IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts Séverine Létuvé, PhD, Stéphane Lajoie-Kadoch, MSc, Séverine Audusseau,

Sputum inflammatory cells from patients with allergic rhinitis and asthma have decreased inflammasome gene expression Willie June Brickey, PhD, Neil.

Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps Javier Milara, PhD, PharmD, Teresa Peiró,

Biology of nasal polyposis

Leukotriene D4 induces gene expression in human monocytes through cysteinyl leukotriene type I receptor Grzegorz Woszczek, MD, PhD, Li-Yuan Chen, PhD,

Human rhinovirus infection enhances airway epithelial cell production of growth factors involved in airway remodeling Richard Leigh, MBChB, PhD, Wale.

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Biju Thomas, MD, Robert Anthony Hirst, PhD, Mina H

IL-10, TGF-β, and glucocorticoid prevent the production of type 2 cytokines in human group 2 innate lymphoid cells Noriko Ogasawara, MD, PhD, Julie A.

Age-related differences in the pathogenesis of chronic rhinosinusitis

Autocrine-regulated airway smooth muscle cell migration is dependent on IL-17–induced growth-related oncogenes Laila A. Al-Alwan, PhD, Ying Chang, PhD,

Julie Negri, BA, S. Brandon Early, BA, John W

Inflammation-mediated upregulation of centrosomal protein 110, a negative modulator of ciliogenesis, in patients with chronic rhinosinusitis Yinyan Lai,

Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis Jennifer K. Mulligan, PhD, Whitney Nagel,

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Presentation transcript:

Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase Jin-Young Min, MD, PhD, Christopher J. Ocampo, MD, PhD, Whitney W. Stevens, MD, PhD, Caroline P.E. Price, BA, Christopher F. Thompson, MD, Tetsuya Homma, MD, PhD, Julia H. Huang, MS, James E. Norton, MS, Lydia A. Suh, BS, Kathryn L. Pothoven, MS, David B. Conley, MD, Kevin C. Welch, MD, Stephanie Shintani-Smith, MD, MS, Anju T. Peters, MD, Leslie C. Grammer, MD, Kathleen E. Harris, BS, Kathryn E. Hulse, PhD, Atsushi Kato, PhD, Nikolai N. Modyanov, PhD, Robert C. Kern, MD, Robert P. Schleimer, PhD, Bruce K. Tan, MD, MS Journal of Allergy and Clinical Immunology Volume 139, Issue 1, Pages 130-141.e11 (January 2017) DOI: 10.1016/j.jaci.2016.07.020 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Increased levels of type 2 inflammatory mediators in nasal tissues and secretions of patients with CRSwNP. Protein levels of IL-13 (A), eotaxin-2 (B), eotaxin-3 (C), and ECP (D) were measured in UT, NPs, and nasal lavage fluid. Dot plots illustrate individual data points, and solid lines represent medians with interquartile ranges. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 IL-13–induced eotaxins protein secretion and inhibitory effects of omeprazole (OME) in airway epithelial cells. A and B, BEAS-2B cells (Fig 2, A) and HNECs (Fig 2, B) were stimulated for 48 hours with IL-13. C and D, BEAS-2B cells (Fig 2, C) and HNECs (Fig 2, D) were pretreated with omeprazole for 2 hours and stimulated for 48 hours with IL-13. Eotaxins (Fig 2, A and B) and eotaxin-3 (Fig 2, C and D) levels in supernatants were measured by using ELISA. Data represent means ± SEMs of 3 (Fig 2, A and C), 15 (Fig 2, B), or 9 (Fig 2, D) independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Eotaxin-2 and eotaxin-3 levels were decreased in patients with CRS taking PPIs at the time of sinus surgery. Protein levels of eotaxin-2 (A) and eotaxin-3 (B) in UT of patients with CRS taking PPIs and those without PPIs were measured by using multiplex immunoassay. Dot plots illustrate individual data points, and solid lines represent medians with interquartile ranges. *P < .05. Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 H,K-ATPase inhibitors decreased IL-13–induced eotaxin-3 protein secretion. A, BEAS-2B cells were pretreated for 2 hours with PPIs, followed by IL-13 stimulation for 48 hours. Eotaxin-3 levels in supernatants were measured by using ELISA. B, Correlations between the measured inhibitory concentration of 50% of PPIs for IL-13–induced eotaxin-3 with published median effective dose of PPIs for gastric pH.42 C, SCH-28080 was used with the same protocol as in Fig 4, A. Data represent means ± SEMs of 3 independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .0001 compared with vehicle-treated/IL-13–stimulated cells (Fig 4, A and C). Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 IL-13–induced responses are mediated by the ngH,K-ATPase. A, After 6 hours of IL-13 stimulation with omeprazole or vehicle in BEAS-2B cells, fluorescence intensity was measured in confocal microscopic images (×60 objective). B, Time course changes in fluorescence intensity in omeprazole (OME)– or vehicle-pretreated BEAS-2B cells after IL-13 stimulation. C and D, IL-13–induced eotaxin-3 mRNA expression was measured in BEAS-2B cells cultured in various [K+]e-containing solution (Fig 5, C) and ATP12A or nontargeting siRNA-transfected HNECs (Fig 5, D). Data represent means ± SEMs of 3 (Fig 5, C) or 8 (Fig 5, D) independent experiments. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Effects of omeprazole (OME) on IL-13–induced STAT6 phosphorylation and eotaxin-3 mRNA stability. A, In IL-13–stimulated BEAS-2B cells with omeprazole or vehicle, phosphorylated STAT6 (pSTAT6) and total STAT6 protein expression were measured by using Western blotting. B, Semiquantitative densitometry data for Fig 6, A (mean ± SEM, n = 3-6). C, Experimental protocol for eotaxin-3 mRNA stability assessment by using real-time PCR. D, Relative eotaxin-3 mRNA expression levels after treatment with actinomycin D, omeprazole, or both. Data represent means ± SEMs (n = 3 each). ****P < .0001. Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Hypothetical model showing the potential role of ngH,K-ATPase in facilitating inhibitory effects of PPIs on IL-13–medicated eotaxin-3 expression. In addition to the canonical IL-13/STAT6 pathway, IL-13–mediated eotaxin-3 expression might be affected by the ngH,K-ATPase activity. The ngH,K-ATPase can be blocked by PPIs and other inhibitors, including SCH-28080, ATP12A siRNA, and [K+]e-free solution, resulting in H+,K+-flux and pHi changes, which might affect expression of IL-13–mediated eotaxin-3. Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 IL-13–induced eotaxin-1, eotaxin-2, and eotaxin-3 gene expression in cultured airway epithelial cells and dose-dependent inhibition of IL-13–induced eotaxin-3 expression by omeprazole (OME). A and B, BEAS-2B cells (Fig E1, A) and HNECs (Fig E1, B; n = 15) were stimulated for 48 hours with IL-13 at escalating doses. C and D, BEAS-2B cells (Fig E1, C) and HNECs (Fig E1, D) were pretreated with omeprazole for 2 hours and stimulated for 48 hours with IL-13 (5 ng/mL). Eotaxins (Fig E1, A and B) or eotaxin-3 (Fig E1, C and D) mRNA expression levels in total RNA from whole-cell extracts were measured by using real-time PCR. Data represent means ± SEMs of 3 (Fig E1, A and C), 15 (Fig E1, B), or 9 (Fig E1, D) independent experiments. *P < .05, **P < .01, ***P < .001, and ****P < .0001 compared with unstimulated cells (Fig E1, A and B) or vehicle-treated/IL-13–stimulated cells (Fig E1, C and D). Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 PPIs did not inhibit mRNA expression of IFN-γ–induced CXCL10, TNF–induced eotaxin-1, and IL-17–induced CXCL1 in BEAS-2B cells. Cells were pretreated with various PPIs for 2 hours and stimulated for 6 hours with IFN-γ (10 ng/mL), TNF (100 ng/mL), or IL-17 (50 ng/mL). IFN-γ–induced CXCL10, TNF–induced eotaxin-1, and IL-17–induced CXCL1 mRNA expression levels in total RNA from cells were measured by using real-time PCR. Data represent means ± SEMs of 3 independent experiments. **P < .01, ***P < .001, and ****P < .0001 compared with vehicle-treated/cytokine-stimulated cells. E, Esomeprazole; L, lansoprazole; O, omeprazole; P, pantoprazole; R, rabeprazole (all at 5 μmol/L). Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Representative Western blot films of ATP12A protein (ngH,K-ATPase) expression in BEAS-2B cells, HNECs, and K-RasVal12–transformed normal rat kidney (KNRK) cells (positive control). Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 SCH-28080 blocked IL-13–induced intracellular alkalization in BEAS-2B cells. Cells were pretreated with SCH-28080 or vehicle for 2 hours before pHrodo Green dye staining. After staining, cells were stimulated with IL-13 at 5 ng/mL. Fluorescence intensities were measured at various times before and after IL-13 stimulation up to 1 hour by using spectrofluorometry. Data represent mean ± SEM percentages of initial values at time zero from 3 independent experiments. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Overall knockdown efficiencies of ATP12A mRNA and protein expression in HNECs. Cells were transfected with 25 pmol of ON-TARGETplus ATP12A siRNA or nontargeting siRNA for 96 hours. ATP12A mRNA expression levels in total RNA from cells were measured by using real-time PCR. Representative Western blot films of ATP12A protein expression in HNECs is shown. The level of ATP12A mRNA was expressed as a percentage of non siRNA transfected value. Data represent means ± SEMs of 7 independent experiments. *P < .05 and ***P < .001. Journal of Allergy and Clinical Immunology 2017 139, 130-141.e11DOI: (10.1016/j.jaci.2016.07.020) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions