title: Janus kinase 1/3 signaling pathways are key initiators of TH2 differentiation and lung allergic responses.
abstract: BACKGROUND
  Janus kinases (JAKs) are regulators of signaling through cytokine receptors. The importance of JAK1/3 signaling on TH2 differentiation and development of lung allergic responses has not been investigated.
  
  
  OBJECTIVE
  We sought to examine a selective JAK1/3 inhibitor (R256) on differentiation of TH subsets in vitro and on development of ovalbumin (OVA)-induced airway hyperresponsiveness (AHR) and inflammation in an experimental model of asthma.
  
  
  METHODS
  A selective JAK1/3 inhibitor was used to assay the importance of this pathway on induction of TH1, TH2, and TH17 differentiation in vitro. In vivo, the effects of inhibiting JAK1/3 signaling were examined by administering the inhibitor during the sensitization or allergen challenge phases in the primary challenge model or just before provocative challenge in the secondary challenge model. Airway inflammation and AHR were examined after the last airway challenge.
  
  
  RESULTS
  In vitro, R256 inhibited differentiation of TH2 but not TH1 or TH17 cells, which was associated with downregulation of signal transducer and activator of transcription (STAT) 6 and STAT5 phosphorylation. However, once polarized, TH2 cells were unaffected by the inhibitor. In vivo, R256 administered during the OVA sensitization phase prevented the development of AHR, airway eosinophilia, mucus hypersecretion, and TH2 cytokine production without changes in TH1 and TH17 cytokine levels, indicating that selective blockade of TH2 differentiation was critical. Inhibitor administration after OVA sensitization but during the challenge phases in the primary or secondary challenge models similarly suppressed AHR, airway eosinophilia, and mucus hypersecretion without any reduction in TH2 cytokine production, suggesting the inhibitory effects were downstream of TH2 cytokine receptor signaling pathways.
  
  
  CONCLUSIONS
  Targeting the TH2-dependent JAK/STAT activation pathway represents a novel therapeutic approach for the treatment of asthma.
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Ashino
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, Calif.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, Calif.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Taylor
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colo.
authors.forename: Anthony
authors.initials: A
authors.lastname: Joetham
authors.affiliation: Rigel Pharmaceuticals, South San Francisco, Calif.
authors.forename: Polly R
authors.initials: PR
authors.lastname: Pine
authors.affiliation: Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colo. Electronic address: gelfande@njhealth.org.
authors.forename: Erwin W
authors.initials: EW
authors.lastname: Gelfand
mesh_terms: D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005260:Female; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*
chemical_list: D000485:Allergens; D047428:Protein Kinase Inhibitors; D053613:Janus Kinase 1; D053616:Janus Kinase 3
keywords: Janus kinase 1/3; T(H)2; asthma