title: Cyclooxygenase-2 regulates Th17 cell differentiation during allergic lung inflammation.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  To determine the role of COX metabolites in regulating Th17 cell 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.
  
  
  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 PGF(2α) and PGI(2) enhanced Th17 cell differentiation of COX-2(-/-) CD4(+) T cells in vitro. The selective COX-2 inhibitor, NS-398, and PGF(2α) receptor and PGI(2) receptor 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 PGI(2) and PGF(2α) through their respective cell surface receptors.
authors.affiliation: Laboratories of Respiratory Biology; National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: J Alyce
authors.initials: JA
authors.lastname: Bradbury
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Dackor
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.forename: Joan P
authors.initials: JP
authors.lastname: Graves
authors.forename: Laura M
authors.initials: LM
authors.lastname: DeGraff
authors.forename: Ping Ming
authors.initials: PM
authors.lastname: Wang
authors.forename: Carl D
authors.initials: CD
authors.lastname: Bortner
authors.forename: Shuichiro
authors.initials: S
authors.lastname: Maruoka
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.forename: Donald N
authors.initials: DN
authors.lastname: Cook
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Tomer
authors.forename: Anton M
authors.initials: AM
authors.lastname: Jetten
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D051545:Cyclooxygenase 1 / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000502:physiology*; D015777:Eicosanoids / Q000378:metabolism; D007249:Inflammation; D020381:Interleukin-17 / Q000378:metabolism; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D011982:Receptors, Prostaglandin / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000502:physiology
chemical_list: D015777:Eicosanoids; C508717:IL17A protein, human; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011982:Receptors, Prostaglandin; D050796:STAT3 Transcription Factor; D010047:Ovalbumin; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2