Chiba Yoshihiko, Todoroki Michiko, Nishida Yuichi, Tanabe Miki, Misawa Miwa
Department of Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
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.
白细胞介素 - 13（IL - 13）是哮喘气道高反应性发展的核心介质之一。信号转导和转录激活因子6（STAT6）是IL - 13激活的主要信号转导因子之一，有人提出IL - 13/STAT6通路可能参与支气管平滑肌（BSM）收缩增强。在本研究中，研究了新型STAT6抑制剂AS1517499对抗原诱导的BSM高反应性发展的影响。在培养的人BSM细胞中，IL - 13（100 ng/ml）引起STAT6磷酸化和RhoA上调，RhoA是一种负责平滑肌收缩Ca2 +致敏的单体GTP酶：这两个事件都被与AS1517499（100 nM）共同孵育所抑制。在主动致敏并用卵清蛋白抗原反复攻击的BALB/c小鼠中，末次抗原攻击后，支气管肺泡灌洗液中IL - 13水平升高，支气管组织中STAT6磷酸化。这些小鼠对乙酰胆碱的BSM收缩性增强，同时支气管组织中RhoA上调。在每次卵清蛋白暴露前1小时腹腔注射AS1517499（10 mg/kg）几乎完全抑制了抗原诱导的RhoA上调和BSM高反应性。还发现对抗原诱导的IL - 13产生有部分但显著的抑制作用。这些发现表明，STAT6抑制剂如AS1517499对RhoA和IL - 13上调的抑制作用可能对哮喘治疗有用。
