A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice

Am J Respir Cell Mol Biol. 2009 Nov;41(5):516-24. doi: 10.1165/rcmb.2008-0163OC. Epub 2009 Feb 6.


Interleukin-13 (IL-13) is one of the central mediators for development of airway hyperresponsiveness in asthma. The signal transducer and activation of transcription 6 (STAT6) is one of the major signal transducers activated by IL-13, and a possible involvement of IL-13/STAT6 pathway in the augmented bronchial smooth muscle (BSM) contraction has been suggested. In the present study, the effect of a novel STAT6 inhibitor, AS1517499, on the development of antigen-induced BSM hyperresponsiveness was investigated. In cultured human BSM cells, IL-13 (100 ng/ml) caused a phosphorylation of STAT6 and an up-regulation of RhoA, a monomeric GTPase responsible for Ca2+ sensitization of smooth muscle contraction: both events were inhibited by co-incubation with AS1517499 (100 nM). In BALB/c mice that were actively sensitized and repeatedly challenged with ovalbumin antigen, an increased IL-13 level in bronchoalveolar lavage fluids and a phosphorylation of STAT6 in bronchial tissues were observed after the last antigen challenge. These mice had an augmented BSM contractility to acetylcholine together with an up-regulation of RhoA in bronchial tissues. Intraperitoneal injections of AS1517499 (10 mg/kg) 1 hour before each ovalbumin exposure inhibited both the antigen-induced up-regulation of RhoA and BSM hyperresponsiveness, almost completely. A partial but significant inhibition of antigen-induced production of IL-13 was also found. These findings suggest that the inhibitory effects of STAT6 inhibitory agents, such as AS1517499, both on RhoA and IL-13 up-regulations might be useful for asthma treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Asthmatic Agents / administration & dosage
  • Anti-Asthmatic Agents / pharmacology*
  • Antigens
  • Asthma / drug therapy*
  • Asthma / immunology
  • Asthma / metabolism
  • Asthma / physiopathology
  • Bronchi / drug effects*
  • Bronchi / immunology
  • Bronchi / metabolism
  • Bronchi / physiopathology
  • Bronchial Hyperreactivity / immunology
  • Bronchial Hyperreactivity / metabolism
  • Bronchial Hyperreactivity / physiopathology
  • Bronchial Hyperreactivity / prevention & control*
  • Bronchoalveolar Lavage Fluid / immunology
  • Bronchoconstriction / drug effects*
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Humans
  • Immunoglobulin E / blood
  • Injections, Intraperitoneal
  • Interleukin-13 / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Muscle, Smooth / drug effects*
  • Muscle, Smooth / immunology
  • Muscle, Smooth / metabolism
  • Muscle, Smooth / physiopathology
  • Ovalbumin
  • Phosphorylation
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology*
  • Recombinant Proteins / metabolism
  • STAT6 Transcription Factor / antagonists & inhibitors*
  • STAT6 Transcription Factor / metabolism
  • Time Factors
  • rho GTP-Binding Proteins / metabolism
  • rhoA GTP-Binding Protein / metabolism


  • 4-(benzylamino)-2-((2-(3-chloro-4-hydroxyphenyl)ethyl)amino)pyrimidine-5-carboxamide
  • Anti-Asthmatic Agents
  • Antigens
  • Interleukin-13
  • Pyrimidines
  • Recombinant Proteins
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Stat6 protein, mouse
  • RHOA protein, human
  • Immunoglobulin E
  • Ovalbumin
  • RhoA protein, mouse
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein