A novel STAT6 inhibitor AS1517499 ameliorates antigen-induced bronchial hypercontractility in mice.
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.
Chiba
Yoshihiko
Y
Department of Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan. chiba@hoshi.ac.jp
Todoroki
Michiko
M
Nishida
Yuichi
Y
Tanabe
Miki
M
Misawa
Miwa
M
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000941:Antigens; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016084:Bronchoconstriction / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007274:Injections, Intraperitoneal; D018793:Interleukin-13 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009130:Muscle, Smooth / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D010047:Ovalbumin; D010766:Phosphorylation; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C544923:4-(benzylamino)-2-((2-(3-chloro-4-hydroxyphenyl)ethyl)amino)pyrimidine-5-carboxamide; D018927:Anti-Asthmatic Agents; D000941:Antigens; D018793:Interleukin-13; D011743:Pyrimidines; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; C066737:RHOA protein, human; D007073:Immunoglobulin E; D010047:Ovalbumin; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein