Cyclooxygenase inhibition during allergic sensitization increases STAT6-independent primary and memory Th2 responses.
Immune sensitization and memory generation are required for the development of allergic inflammation. Our previous studies demonstrate that the cyclooxygenase (COX) metabolic pathway is actively involved in allergic responses and COX inhibition increases allergic airway inflammation in a STAT6-independent fashion. To test the hypothesis that COX inhibition augments allergic inflammation by enhancing immune sensitization and memory, we sensitized STAT6 knockout mice with an i.p. injection of OVA with aluminum hydroxide as an adjuvant and treated the mice with the COX inhibitor indomethacin or vehicle for analyses of the primary and memory immune responses. We found that COX inhibition during immune sensitization, but not the allergic challenge phase, was necessary and sufficient to increase allergic inflammation. COX inhibition during sensitization increased the numbers of mature dendritic cells and activated CD4 T cells in the spleen and augmented OVA-specific IL-5 and IL-13 responses of the splenic CD4 T cells at day 5 after sensitization. COX inhibition during sensitization also augmented allergic Th2 response to OVA challenge 90 days after the sensitization. Therefore, COX inhibition during allergic sensitization augments allergic responses by enhancing Th2 cell activation and memory generation and the proallergic effect is STAT6-independent. These findings provide a mechanistic explanation for the increased allergic inflammation previously shown in the mice treated with COX inhibitors and in COX-deficient mice and suggest that use of COX-inhibiting drugs during initial allergen exposure may increase the risk of developing allergic responses.
Zhou
Weisong
W
Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. weisong.zhou@vanderbilt.edu
Newcomb
Dawn C
DC
Moore
Martin L
ML
Goleniewska
Kasia
K
O'Neal
Jamye F
JF
Peebles
R Stokes
RS
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects / Q000235:genetics; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015848:Interleukin-5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology*; D013997:Time Factors
D016861:Cyclooxygenase Inhibitors; D018793:Interleukin-13; D015848:Interleukin-5; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin