title: Cyclooxygenase inhibition abrogates aeroallergen-induced immune tolerance by suppressing prostaglandin I2 receptor signaling.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn. Electronic address: weisong.zhou@vanderbilt.edu.
authors.forename: Weisong
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Kasia
authors.initials: K
authors.lastname: Goleniewska
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Dulek
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Shinji
authors.initials: S
authors.lastname: Toki
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Lotz
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Newcomb
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Madison G
authors.initials: MG
authors.lastname: Boswell
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.affiliation: Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Ginger L
authors.initials: GL
authors.lastname: Milne
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, Atlanta, Ga.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Moore
authors.affiliation: Department of Pharmacology, University of Pennsylvania, Philadelphia, Pa.
authors.forename: Garret A
authors.initials: GA
authors.lastname: FitzGerald
authors.affiliation: Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
mesh_terms: D000397:Air Pollution / Q000009:adverse effects; D000485:Allergens / Q000009:adverse effects / Q000276:immunology; D000818:Animals; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D011464:Epoprostenol / Q000378:metabolism*; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D007108:Immune Tolerance; D007213:Indomethacin / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D044006:Receptors, Epoprostenol / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000485:Allergens; D004791:Enzyme Inhibitors; D044006:Receptors, Epoprostenol; D010047:Ovalbumin; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin
keywords: PGI(2); allergy; immune tolerance