Cyclooxygenase-2 regulates Th17 cell differentiation during allergic lung inflammation

Academic Article

Abstract

  • Rationale: Th17 cells comprise a distinct lineage of proinflammatory T helper cells that are major contributors to allergic responses. It is unknown whether cyclooxygenase (COX)-derived eicosanoids regulate Th17 cells during allergic lung inflammation. Objectives: To determine the role of COX metabolites in regulating Th17cell differentiation and function during allergic lung inflammation. Methods: COX-1-/-, COX-2-/-, and wild-type mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th17 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time polymerase chain reaction, 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: Th17 cell differentiation in lung, lymph nodes, and bronchoalveolar lavage fluid was significantly lower in COX-2-/- mice after ovalbumin sensitization and exposure in vivo. In vitro studies revealed significantly impaired Th17 cell differentiation of COX-2-/- naive CD4+ T cells with decreased Stat3 phosphorylation and RORγt expression. Synthetic PGF2α and PGI2enhanced Th17 cell differentiation of COX-2-/- CD4+ T cells in vitro. The selective COX-2 inhibitor, NS-398, and PGF2α receptor and PGI2receptor siRNA knockdown significantly decreased Th17 cell differentiation in vitro. Administration of synthetic PGs restored accumulation of Th17 cells in lungs of allergic COX-2-/- mice in vivo. Conclusions: COX-2 is a critical regulator of Th17 cell differentiation during allergic lung inflammation via autocrine signaling of PGI2 and PGF2α through their respective cell surface receptors.
  • Digital Object Identifier (doi)

    Pubmed Id

  • 9822726
  • Author List

  • Li H; Alyce Bradbury J; Dackor RT; Edin ML; Graves JP; DeGraff LM; Wang PM; Bortner CD; Maruoka S; Lih FB
  • Start Page

  • 37
  • End Page

  • 49
  • Volume

  • 184
  • Issue

  • 1