title: Cyclooxygenase inhibition augments allergic inflammation through CD4-dependent, STAT6-independent mechanisms.
abstract: Nonselective cyclooxygenase (COX) inhibition during the development of allergic disease in a murine model causes an increase in type 2 cytokines and lung eosinophilia; however, the mechanisms responsible for this augmented allergen-induced inflammation have not been examined. Ab depletion of CD4 and CD8 cells revealed that the heightened allergic inflammation caused by COX inhibition was CD4, but not CD8, dependent. Allergen sensitization and airway challenge alone led to undetectable levels of IL-5 and IL-13 in the lungs of IL-4, IL-4Ralpha, and STAT6 knockout (KO) mice, but COX inhibition during the development of allergic inflammation resulted in wild-type levels of IL-5 and IL-13 and heightened airway eosinophilia in each of the three KO mice. These results indicate that the effect of COX inhibition was independent of signaling through IL-4, IL-4Ralpha, and STAT6. However, whereas COX inhibition increased IgE levels in allergic wild-type mice, IgE levels were undetectable in IL-4, IL-4Ralpha, and STAT6 KO mice, suggesting that IL-13 alone is not a switch factor for IgE synthesis in this model. These results illustrate the central role played by products derived from the COX pathway in the regulation of allergic immune responses.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Koichi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: James R
authors.initials: JR
authors.lastname: Sheller
authors.forename: Jason D
authors.initials: JD
authors.lastname: Morrow
authors.forename: Robert D
authors.initials: RD
authors.lastname: Collins
authors.forename: Kasia
authors.initials: K
authors.lastname: Goleniewska
authors.forename: Jamye
authors.initials: J
authors.lastname: O'Neal
authors.forename: Weisong
authors.initials: W
authors.lastname: Zhou
authors.forename: Shaoquan
authors.initials: S
authors.lastname: Ji
authors.forename: Daphne B
authors.initials: DB
authors.lastname: Mitchell
authors.forename: Barney S
authors.initials: BS
authors.lastname: Graham
authors.forename: R Stokes
authors.initials: RS
authors.lastname: Peebles
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D016207:Cytokines / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D006967:Hypersensitivity / Q000276:immunology*; D007073:Immunoglobulin E / Q000096:biosynthesis; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000276:immunology; D018793:Interleukin-13 / Q000032:analysis / Q000276:immunology; D015848:Interleukin-5 / Q000032:analysis / Q000276:immunology; D008171:Lung Diseases / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000276:immunology* / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000276:immunology; D050800:STAT6 Transcription Factor; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology*
chemical_list: D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D018793:Interleukin-13; D015848:Interleukin-5; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D007073:Immunoglobulin E; D010047:Ovalbumin; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin