Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I-2 receptor signaling

• Type of Material: Article
• Authors: Weisong Zhou, Vanderbilt University; Kasia Goleniewska, Vanderbilt University; Jian Zhang, Vanderbilt University; Daniel E. Dulek, Vanderbilt University; Shinji Toki, Vanderbilt University; Matthew T. Lotz, Vanderbilt University; Dawn C. Newcomb, Vanderbilt University; Madison G. Boswell, Vanderbilt University; Vasiliy V. Polosukhin, Vanderbilt University; Ginger L. Milne, Vanderbilt University; Pingsheng Wu, Vanderbilt University; Martin L Moore, Emory University; Garret A. FitzGerald, University of Pennsylvania; R. Stokes Peebles, Jr., Vanderbilt University
• Language: English
• Date: 2014-09-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jaci.2014.06.004
• Title of Journal or Parent Work: Journal of Allergy and Clinical Immunology
• ISSN: 0091-6749
• Volume: 134
• Issue: 3
• Start Page: 698
• End Page: 705.e5
• Grant/Funding Information: This study was supported by National Institute of Health grants R01 AI 111820, 2I01BX000624, U19 AI 095227-02, R01 HL 090664-04 and R56 AI076411 and Veteran Affairs grant 2I01BX000624.
• Keywords: Science & Technology; CHALLENGE; allergy; SENSITIZATION; CYTOKINE PRODUCTION; Life Sciences & Biomedicine; BOUND TGF-BETA; AIRWAY HYPERRESPONSIVENESS; INCREASES; immune tolerance; Immunology; PGI(2); ASTHMA; DEFICIENT MICE; ALLERGIC INFLAMMATION; REGULATORY T-CELLS; Allergy
• Research Categories: Health Sciences, Immunology

Abstract

BACKGROUND: The prevalence of allergic diseases has doubled in developed countries in the past several decades. Cyclooxygenase (COX)-inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses. However, whether COX inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known.OBJECTIVE: To determine the role of the COX pathway and prostaglandin I2 (PGI2) signaling through the PGI2 receptor (IP) in aeroallergen-induced immune tolerance.METHODS: Wild-type (WT) BALB/c mice and IP knockout mice were aerosolized with ovalbumin (OVA) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA/alum. The COX inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase. Two weeks after sensitization, the mice were challenged with OVA aerosols. Mouse bronchoalveolar lavage fluid was harvested for cell counts and TH2 cytokine measurements.RESULTS: WT mice treated with indomethacin had greater numbers of total cells, eosinophils, and lymphocytes, and increased IL-5 and IL-13 protein expression in BAL fluid compared to vehicle-treated mice. Similarly, IP knockout mice had augmented inflammation and TH2 cytokine responses compared to WT mice. In contrast, the PGI2 analog cicaprost attenuated the anti-tolerance effect of COX inhibition.CONCLUSION: COX inhibition abrogated immune tolerance by suppressing PGI2 IP signaling, suggesting that PGI2 signaling promotes immune tolerance and that clinical use of COX-inhibiting drugs may increase the risk of developing allergic diseases.