Interleukin-13 augments bronchial smooth muscle contractility with an up-regulation of RhoA protein.
Interleukin-13 (IL-13) is one of the central mediators for development of airway hyperresponsiveness in asthma. However, its effect on bronchial smooth muscle (BSM) is not well known. Recent studies revealed an involvement of RhoA/Rho-kinase in BSM contraction, and this pathway has now been proposed as a new target for asthma therapy. To elucidate the role of IL-13 on the induction of BSM hyperresponsiveness, effects of IL-13 on contractility and RhoA expression in BSMs were investigated. Male BALB/c mice were sensitized and repeatedly challenged with ovalbumin antigen. In the repeatedly antigen-challenged mice, marked airway inflammation and BSM hyperresponsiveness with an up-regulation of IL-13 in bronchoalveolar lavage fluids were observed. In cultured human BSM cells, IL-13 caused an up-regulation of RhoA. The IL-13-induced up-regulation of RhoA was inhibited by leflunomide, an inhibitor of signal transducer and activator of transcription 6 (STAT6). In isolated BSM tissues of naive mice, the contractility was significantly enhanced by organ culture in the presence of IL-13. Moreover, in vivo treatment of airways with IL-13 by intranasal instillation caused a BSM hyperresponsiveness with an up-regulation of RhoA in naive mice. These findings suggest that IL-13/STAT6 signaling is critical for development of antigen-induced BSM hyperresponsiveness and that agents that specifically inhibit this pathway in BSM may provide a novel strategy for the treatment of asthma.
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
Nakazawa
Shuji
S
Todoroki
Michiko
M
Shinozaki
Koji
K
Sakai
Hiroyasu
H
Misawa
Miwa
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001249:Asthma / Q000378:metabolism* / Q000473:pathology; D018893:Bronchoalveolar Lavage; D002460:Cell Line; D004195:Disease Models, Animal; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism* / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D000077339:Leflunomide; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000378:metabolism* / Q000473:pathology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis*; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018793:Interleukin-13; D007555:Isoxazoles; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; C066737:RHOA protein, human; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000077339:Leflunomide