Department of Pharmacology, School of Pharmacy, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Pharmacol Res. 2010 Feb;61(2):188-92. doi: 10.1016/j.phrs.2009.10.003. Epub 2009 Oct 24.
Interleukin-4 (IL-4) is believed to play a role in allergic bronchial asthma, and has been suggested to cause hyperresponsiveness of airway smooth muscle. In the present study, the effects of IL-4 on the expression of RhoA protein, a monomeric GTP-binding protein that contributes to the contraction of smooth muscle, were determined in cultured human bronchial smooth muscle cells (hBSMCs). Incubation of hBSMCs with IL-4 (100ng/mL) caused a distinct phosphorylation of signal transducer and activator of transcription 6 (STAT6), a major signal transducer activated by IL-4, indicating that IL-4 is capable of activating signal transduction in the hBSMCs directly. IL-4 also caused a significant increase in the expression level of RhoA protein: the peak of the upregulation of RhoA protein was observed at 12-24h after the IL-4 treatment. Both the phosphorylation of STAT6 and the upregulation of RhoA protein induced by IL-4 were inhibited by the co-incubation with AS1517499, a selective inhibitor of STAT6, in a concentration-dependent fashion. These findings suggest that IL-4 is capable of inducing an upregulation of RhoA via an activation of STAT6 in cultured hBSMCs. The RhoA upregulation induced by IL-4, one of the Th2 cytokines upregulated in the airways of allergic bronchial asthmatics, might result in an augmentation of bronchial smooth muscle contractility, that is one of the causes of airway hyperresponsiveness.
白细胞介素-4（IL-4）被认为在过敏性支气管哮喘中起作用，并被认为导致气道平滑肌的高反应性。在本研究中，确定了白细胞介素-4（IL-4）对培养的人支气管平滑肌细胞（hBSMC）中RhoA 蛋白表达的影响，RhoA 蛋白是一种单体 GTP 结合蛋白，有助于平滑肌收缩。IL-4（100ng/mL）孵育引起信号转导和转录激活因子 6（STAT6）的明显磷酸化，STAT6 是 IL-4 激活的主要信号转导物，表明 IL-4 能够直接激活 hBSMC 中的信号转导。IL-4 还导致 RhoA 蛋白表达水平的显著增加：在 IL-4 处理后 12-24 小时观察到 RhoA 蛋白上调的峰值。IL-4 诱导的 STAT6 磷酸化和 RhoA 蛋白上调均被 AS1517499 抑制，AS1517499 是 STAT6 的选择性抑制剂，呈浓度依赖性。这些发现表明，IL-4 通过激活 STAT6 能够诱导培养的 hBSMC 中 RhoA 的上调。IL-4 诱导的 RhoA 上调，是过敏性支气管哮喘气道中上调的 Th2 细胞因子之一，可能导致支气管平滑肌收缩性增强，这是气道高反应性的原因之一。
