A Novel STAT6 Inhibitor AS1517499 Ameliorates Antigen-Induced Bronchial Hypercontractility in Mice
A Novel STAT6 Inhibitor AS1517499 Ameliorates Antigen-Induced Bronchial Hypercontractility in Mice
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DOI：
10.1165/rcmb.2008-0163oc
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发表时间：
2009-11-01
影响因子：
6.4
通讯作者：
Misawa, Miwa
中科院分区：
文献类型：
--
作者：
Chiba, Yoshihiko;Todoroki, Michiko;Misawa, Miwa
白细胞介素-13（IL-13）是哮喘气道高反应性发生发展的中枢介质之一。信号转导和转录激活因子6（STAT 6）是IL-13激活的主要信号转导因子之一，IL-13/STAT 6通路可能参与增强支气管平滑肌（BSM）收缩。在本研究中，研究了新型STAT 6抑制剂AS 1517499对抗原诱导的BSM高反应性的影响。在培养的人BSM细胞中，IL-13（100 ng/ml）引起STAT 6磷酸化和RhoA上调，RhoA是一种负责平滑肌收缩的Ca 2+敏化的单体GT3：与AS 1517499（100 nM）共孵育可抑制这两种事件。在主动致敏的BALB/c小鼠中，用卵白蛋白抗原反复激发，在最后一次抗原激发后观察到支气管肺泡灌洗液中IL-13水平升高和支气管组织中STAT 6磷酸化。这些小鼠具有增强的BSM对乙酰胆碱的收缩性以及支气管组织中RhoA的上调。在每次卵清蛋白暴露前1小时腹膜内注射AS 1517499（10 mg/kg）几乎完全抑制抗原诱导的RhoA和BSM高反应性上调。这些结果表明，STAT 6抑制剂，如AS 1517499，对RhoA和IL-13上调的抑制作用可能对哮喘治疗有用。
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) I 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.