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, Christopher J. Ocampo, Whitney Stevens, Caroline P.E. Price, Christopher F. Thompson, Tetsuya Homma, Julia H. Huang, James E. Norton, Lydia A. Suh, Kathryn L. Pothoven, David B Conley Jr, Kevin Christian Welch, Stephanie Shintani Smith, Anju Tripathi Peters, Leslie C Grammer III, Kathleen E. Harris, Kathryn E Hulse, Atsushi Kato, Nikolai N. Modyanov, Robert C Kern & 2 others Robert P Schleimer, Bruce Kuang-Huay Tan*

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by tissue eosinophilia that is associated with poor prognosis. Recent findings that proton pump inhibitors (PPIs) directly modulate the expression of eotaxin-3, an eosinophil chemoattractant, in patients with eosinophilic diseases suggest therapeutic potential for PPIs in those with CRSwNP. Objective We assessed the effect of type 2 mediators, particularly IL-13 and eotaxin-3, on tissue eosinophilia and disease severity in patients with chronic rhinosinusitis (CRS). Further investigation focused on PPI suppression of eotaxin-3 expression in vivo and in vitro, with exploration of underlying mechanisms. Methods Type 2 mediator levels in nasal tissues and secretions were measured by using a multiplex immunoassay. Eotaxin-3 and other chemokines expressed in IL-13–stimulated human sinonasal epithelial cells (HNECs) and BEAS-2B cells with or without PPIs were assessed by using ELISA, Western blotting, real-time PCR, and intracellular pH imaging. Results Nasal tissues and secretions from patients with CRSwNP had increased IL-13, eotaxin-2, and eotaxin-3 levels, and these were positively correlated with tissue eosinophil cationic protein levels and radiographic scores in patients with CRS (P < .05). IL-13 stimulation of HNECs and BEAS-2B cells dominantly induced eotaxin-3 expression, which was significantly inhibited by PPIs (P < .05). Patients with CRS taking PPIs also showed lower in vivo eotaxin-3 levels compared with those without PPIs (P < .05). Using intracellular pH imaging and altering extracellular K+, we found that IL-13 enhanced H+,K+-exchange, which was blocked by PPIs and the mechanistically unrelated H,K-ATPase inhibitor, SCH-28080. Furthermore, knockdown of ATP12A (gene for the nongastric H,K-ATPase) significantly attenuated IL-13–induced eotaxin-3 expression in HNECs. PPIs also had effects on accelerating IL-13–induced eotaxin-3 mRNA decay. Conclusion Our results demonstrated that PPIs reduce IL-13–induced eotaxin-3 expression by airway epithelial cells. Furthermore, mechanistic studies suggest that the nongastric H,K-ATPase is necessary for IL-13–mediated epithelial responses, and its inhibitors, including PPIs, might be of therapeutic value in patients with CRSwNP by reducing epithelial production of eotaxin-3.

Original languageEnglish (US)
Pages (from-to)130-141.e11
JournalJournal of Allergy and Clinical Immunology
Volume139
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Nasal Polyps
Proton-Translocating ATPases
Proton Pump Inhibitors
Interleukin-13
Epithelial Cells
Eosinophilia
Nose
Chemokine CCL24
Eosinophil Cationic Protein
Gene Knockdown Techniques
Chemotactic Factors
RNA Stability
Chemokines
Immunoassay
Eosinophils
Real-Time Polymerase Chain Reaction
Western Blotting
Enzyme-Linked Immunosorbent Assay

Keywords

  • Chronic rhinosinusitis
  • H(+)-K(+)-exchanging ATPase
  • IL-13
  • eosinophils
  • eotaxin-1/CCL11
  • eotaxin-2/CCL24
  • eotaxin-3/CCL26
  • epithelial cells
  • omeprazole
  • proton pump inhibitors

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

@article{467e4ebe7654449c9ff8228a068b3873,
title = "Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase",
abstract = "Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by tissue eosinophilia that is associated with poor prognosis. Recent findings that proton pump inhibitors (PPIs) directly modulate the expression of eotaxin-3, an eosinophil chemoattractant, in patients with eosinophilic diseases suggest therapeutic potential for PPIs in those with CRSwNP. Objective We assessed the effect of type 2 mediators, particularly IL-13 and eotaxin-3, on tissue eosinophilia and disease severity in patients with chronic rhinosinusitis (CRS). Further investigation focused on PPI suppression of eotaxin-3 expression in vivo and in vitro, with exploration of underlying mechanisms. Methods Type 2 mediator levels in nasal tissues and secretions were measured by using a multiplex immunoassay. Eotaxin-3 and other chemokines expressed in IL-13–stimulated human sinonasal epithelial cells (HNECs) and BEAS-2B cells with or without PPIs were assessed by using ELISA, Western blotting, real-time PCR, and intracellular pH imaging. Results Nasal tissues and secretions from patients with CRSwNP had increased IL-13, eotaxin-2, and eotaxin-3 levels, and these were positively correlated with tissue eosinophil cationic protein levels and radiographic scores in patients with CRS (P < .05). IL-13 stimulation of HNECs and BEAS-2B cells dominantly induced eotaxin-3 expression, which was significantly inhibited by PPIs (P < .05). Patients with CRS taking PPIs also showed lower in vivo eotaxin-3 levels compared with those without PPIs (P < .05). Using intracellular pH imaging and altering extracellular K+, we found that IL-13 enhanced H+,K+-exchange, which was blocked by PPIs and the mechanistically unrelated H,K-ATPase inhibitor, SCH-28080. Furthermore, knockdown of ATP12A (gene for the nongastric H,K-ATPase) significantly attenuated IL-13–induced eotaxin-3 expression in HNECs. PPIs also had effects on accelerating IL-13–induced eotaxin-3 mRNA decay. Conclusion Our results demonstrated that PPIs reduce IL-13–induced eotaxin-3 expression by airway epithelial cells. Furthermore, mechanistic studies suggest that the nongastric H,K-ATPase is necessary for IL-13–mediated epithelial responses, and its inhibitors, including PPIs, might be of therapeutic value in patients with CRSwNP by reducing epithelial production of eotaxin-3.",
keywords = "Chronic rhinosinusitis, H(+)-K(+)-exchanging ATPase, IL-13, eosinophils, eotaxin-1/CCL11, eotaxin-2/CCL24, eotaxin-3/CCL26, epithelial cells, omeprazole, proton pump inhibitors",
author = "Min, {Jin Young} and Ocampo, {Christopher J.} and Whitney Stevens and Price, {Caroline P.E.} and Thompson, {Christopher F.} and Tetsuya Homma and Huang, {Julia H.} and Norton, {James E.} and Suh, {Lydia A.} and Pothoven, {Kathryn L.} and {Conley Jr}, {David B} and Welch, {Kevin Christian} and Smith, {Stephanie Shintani} and Peters, {Anju Tripathi} and {Grammer III}, {Leslie C} and Harris, {Kathleen E.} and Hulse, {Kathryn E} and Atsushi Kato and Modyanov, {Nikolai N.} and Kern, {Robert C} and Schleimer, {Robert P} and Tan, {Bruce Kuang-Huay}",
year = "2017",
month = "1",
day = "1",
doi = "10.1016/j.jaci.2016.07.020",
language = "English (US)",
volume = "139",
pages = "130--141.e11",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "1",

}

Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps : Possible role of the nongastric H,K-ATPase. / Min, Jin Young; Ocampo, Christopher J.; Stevens, Whitney; Price, Caroline P.E.; Thompson, Christopher F.; Homma, Tetsuya; Huang, Julia H.; Norton, James E.; Suh, Lydia A.; Pothoven, Kathryn L.; Conley Jr, David B; Welch, Kevin Christian; Smith, Stephanie Shintani; Peters, Anju Tripathi; Grammer III, Leslie C; Harris, Kathleen E.; Hulse, Kathryn E; Kato, Atsushi; Modyanov, Nikolai N.; Kern, Robert C; Schleimer, Robert P; Tan, Bruce Kuang-Huay.

In: Journal of Allergy and Clinical Immunology, Vol. 139, No. 1, 01.01.2017, p. 130-141.e11.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps

T2 - Possible role of the nongastric H,K-ATPase

AU - Min, Jin Young

AU - Ocampo, Christopher J.

AU - Stevens, Whitney

AU - Price, Caroline P.E.

AU - Thompson, Christopher F.

AU - Homma, Tetsuya

AU - Huang, Julia H.

AU - Norton, James E.

AU - Suh, Lydia A.

AU - Pothoven, Kathryn L.

AU - Conley Jr, David B

AU - Welch, Kevin Christian

AU - Smith, Stephanie Shintani

AU - Peters, Anju Tripathi

AU - Grammer III, Leslie C

AU - Harris, Kathleen E.

AU - Hulse, Kathryn E

AU - Kato, Atsushi

AU - Modyanov, Nikolai N.

AU - Kern, Robert C

AU - Schleimer, Robert P

AU - Tan, Bruce Kuang-Huay

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by tissue eosinophilia that is associated with poor prognosis. Recent findings that proton pump inhibitors (PPIs) directly modulate the expression of eotaxin-3, an eosinophil chemoattractant, in patients with eosinophilic diseases suggest therapeutic potential for PPIs in those with CRSwNP. Objective We assessed the effect of type 2 mediators, particularly IL-13 and eotaxin-3, on tissue eosinophilia and disease severity in patients with chronic rhinosinusitis (CRS). Further investigation focused on PPI suppression of eotaxin-3 expression in vivo and in vitro, with exploration of underlying mechanisms. Methods Type 2 mediator levels in nasal tissues and secretions were measured by using a multiplex immunoassay. Eotaxin-3 and other chemokines expressed in IL-13–stimulated human sinonasal epithelial cells (HNECs) and BEAS-2B cells with or without PPIs were assessed by using ELISA, Western blotting, real-time PCR, and intracellular pH imaging. Results Nasal tissues and secretions from patients with CRSwNP had increased IL-13, eotaxin-2, and eotaxin-3 levels, and these were positively correlated with tissue eosinophil cationic protein levels and radiographic scores in patients with CRS (P < .05). IL-13 stimulation of HNECs and BEAS-2B cells dominantly induced eotaxin-3 expression, which was significantly inhibited by PPIs (P < .05). Patients with CRS taking PPIs also showed lower in vivo eotaxin-3 levels compared with those without PPIs (P < .05). Using intracellular pH imaging and altering extracellular K+, we found that IL-13 enhanced H+,K+-exchange, which was blocked by PPIs and the mechanistically unrelated H,K-ATPase inhibitor, SCH-28080. Furthermore, knockdown of ATP12A (gene for the nongastric H,K-ATPase) significantly attenuated IL-13–induced eotaxin-3 expression in HNECs. PPIs also had effects on accelerating IL-13–induced eotaxin-3 mRNA decay. Conclusion Our results demonstrated that PPIs reduce IL-13–induced eotaxin-3 expression by airway epithelial cells. Furthermore, mechanistic studies suggest that the nongastric H,K-ATPase is necessary for IL-13–mediated epithelial responses, and its inhibitors, including PPIs, might be of therapeutic value in patients with CRSwNP by reducing epithelial production of eotaxin-3.

AB - Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by tissue eosinophilia that is associated with poor prognosis. Recent findings that proton pump inhibitors (PPIs) directly modulate the expression of eotaxin-3, an eosinophil chemoattractant, in patients with eosinophilic diseases suggest therapeutic potential for PPIs in those with CRSwNP. Objective We assessed the effect of type 2 mediators, particularly IL-13 and eotaxin-3, on tissue eosinophilia and disease severity in patients with chronic rhinosinusitis (CRS). Further investigation focused on PPI suppression of eotaxin-3 expression in vivo and in vitro, with exploration of underlying mechanisms. Methods Type 2 mediator levels in nasal tissues and secretions were measured by using a multiplex immunoassay. Eotaxin-3 and other chemokines expressed in IL-13–stimulated human sinonasal epithelial cells (HNECs) and BEAS-2B cells with or without PPIs were assessed by using ELISA, Western blotting, real-time PCR, and intracellular pH imaging. Results Nasal tissues and secretions from patients with CRSwNP had increased IL-13, eotaxin-2, and eotaxin-3 levels, and these were positively correlated with tissue eosinophil cationic protein levels and radiographic scores in patients with CRS (P < .05). IL-13 stimulation of HNECs and BEAS-2B cells dominantly induced eotaxin-3 expression, which was significantly inhibited by PPIs (P < .05). Patients with CRS taking PPIs also showed lower in vivo eotaxin-3 levels compared with those without PPIs (P < .05). Using intracellular pH imaging and altering extracellular K+, we found that IL-13 enhanced H+,K+-exchange, which was blocked by PPIs and the mechanistically unrelated H,K-ATPase inhibitor, SCH-28080. Furthermore, knockdown of ATP12A (gene for the nongastric H,K-ATPase) significantly attenuated IL-13–induced eotaxin-3 expression in HNECs. PPIs also had effects on accelerating IL-13–induced eotaxin-3 mRNA decay. Conclusion Our results demonstrated that PPIs reduce IL-13–induced eotaxin-3 expression by airway epithelial cells. Furthermore, mechanistic studies suggest that the nongastric H,K-ATPase is necessary for IL-13–mediated epithelial responses, and its inhibitors, including PPIs, might be of therapeutic value in patients with CRSwNP by reducing epithelial production of eotaxin-3.

KW - Chronic rhinosinusitis

KW - H(+)-K(+)-exchanging ATPase

KW - IL-13

KW - eosinophils

KW - eotaxin-1/CCL11

KW - eotaxin-2/CCL24

KW - eotaxin-3/CCL26

KW - epithelial cells

KW - omeprazole

KW - proton pump inhibitors

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UR - http://www.scopus.com/inward/citedby.url?scp=85001055745&partnerID=8YFLogxK

U2 - 10.1016/j.jaci.2016.07.020

DO - 10.1016/j.jaci.2016.07.020

M3 - Article

VL - 139

SP - 130-141.e11

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 1

ER -