Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling.

Zhou W, Goleniewska K, Zhang J, Dulek DE, Toki S, Lotz MT, Newcomb DC, Boswell MG, Polosukhin VV, Milne GL, Wu P, Moore ML, FitzGerald GA, Peebles RS
J Allergy Clin Immunol. 2014 134 (3): 698-705.e5

PMID: 25042746 · PMCID: PMC4358822 · DOI:10.1016/j.jaci.2014.06.004

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.

Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

MeSH Terms (18)

Air Pollution Allergens Animals Enzyme Inhibitors Epoprostenol Humans Hypersensitivity Immune Tolerance Indomethacin Mice Mice, 129 Strain Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Ovalbumin Prostaglandin-Endoperoxide Synthases Receptors, Epoprostenol Signal Transduction

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