title: Cyclooxygenase-2 inhibits T helper cell type 9 differentiation during allergic lung inflammation via down-regulation of IL-17RB.
abstract: BACKGROUND
  Helper CD4(+) T cell subsets, including IL-9- and IL-10-producing T helper cell type 9 (Th9) cells, exist under certain inflammatory conditions. Cyclooxygenase (COX)-1 and COX-2 play important roles in allergic lung inflammation and asthma. It is unknown whether COX-derived eicosanoids regulate Th9 cells during allergic lung inflammation.
  
  
  OBJECTIVE
  To determine the role of COX metabolites in regulating Th9 cell differentiation and function during allergic lung inflammation.
  
  
  METHODS
  COX-1(-/-), COX-2(-/-), and wild-type (WT) mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th9 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time PCR, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown.
  
  
  RESULTS
  Experimental endpoints were not different between COX-1(-/-) and WT mice; however, the percentage of IL-9(+) CD4(+) T cells was increased in lung, bronchoalveolar lavage fluid, lymph nodes, and blood of allergic COX-2(-/-) mice relative to WT. Bronchoalveolar lavage fluid IL-9 and IL-10, serum IL-9, and lung IL-17RB levels were significantly increased in allergic COX-2(-/-) mice or in WT mice treated with COX-2 inhibitors. IL-9, IL-10, and IL-17RB expression in vivo was inhibited by PGD2 and PGE2, which also reduced Th9 cell differentiation of murine and human naive CD4(+) T cells in vitro. Inhibition of protein kinase A significantly increased Th9 cell differentiation of naive CD4(+) T cells isolated from WT mice in vitro.
  
  
  CONCLUSIONS
  COX-2-derived PGD2 and PGE2 regulate Th9 cell differentiation by suppressing IL-17RB expression via a protein kinase A-dependent mechanism.
authors: Laboratory of Respiratory Biology, Division of Intramural Research, National Institutes of Health/National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
authors: Hong
authors: H
authors: Li
authors: Matthew L
authors: ML
authors: Edin
authors: J Alyce
authors: JA
authors: Bradbury
authors: Joan P
authors: JP
authors: Graves
authors: Laura M
authors: LM
authors: DeGraff
authors: Artiom
authors: A
authors: Gruzdev
authors: Jennifer
authors: J
authors: Cheng
authors: Ryan T
authors: RT
authors: Dackor
authors: Ping Ming
authors: PM
authors: Wang
authors: Carl D
authors: CD
authors: Bortner
authors: Stavros
authors: S
authors: Garantziotis
authors: Anton M
authors: AM
authors: Jetten
authors: Darryl C
authors: DC
authors: Zeldin
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology*; D052246:Cyclooxygenase 2 Inhibitors / Q000276:immunology*; D016207:Cytokines / Q000032:analysis; D015777:Eicosanoids / Q000276:immunology / Q000502:physiology; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation / Q000276:immunology; D008168:Lung / Q000276:immunology*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D023421:Models, Animal; D060888:Real-Time Polymerase Chain Reaction; D053722:Receptors, Interleukin-17 / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D015777:Eicosanoids; C485810:Il17rb protein, mouse; D053722:Receptors, Interleukin-17