Cyclooxygenase-2 inhibits T helper cell type 9 differentiation during allergic lung inflammation via down-regulation of IL-17RB

Academic Article

Abstract

  • Rationale:HelperCD4+ Tcell subsets, includingIL-9-andIL-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. Objectives: 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. Measurements and Main Results: Experimental end points 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.
  • Digital Object Identifier (doi)

    Pubmed Id

  • 9671945
  • Author List

  • Li H; Edin ML; Bradbury JA; Graves JP; DeGraff LM; Gruzdev A; Cheng J; Dackor RT; Wang PM; Bortner CD
  • Start Page

  • 812
  • End Page

  • 822
  • Volume

  • 187
  • Issue

  • 8