T-bet is induced by interferon-γ to mediate chemokine secretion and migration in human airway smooth muscle cells.
T-bet is induced by interferon-γ to mediate chemokine secretion and migration in human airway smooth muscle cells.
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T-bet 由干扰素-γ 诱导，介导人气道平滑肌细胞的趋化因子分泌和迁移。
DOI：
10.1152/ajplung.00163.2010
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Singer,CherieA
中科院分区：
文献类型：
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作者：
Singer,CherieA
辅助性t (Th)1和Th2细胞因子产生之间的不适当平衡是导致气道疾病的炎症变化的基础。T-box转录因子T-bet的表达调节Th细胞的分化和Th1细胞因子的产生，特别是IFNγ。t- bet缺陷小鼠出现气道高反应性，气道重塑，并在过量产生Th2细胞因子时表现出IFNγ产生缺陷。哮喘患者气道中的T-bet也减少，提示T-bet表达或活性的丧失促进了炎症性气道疾病的发展。我们提出的新数据表明，T-bet在人气道平滑肌细胞（ASMC）中被IFNγ诱导表达。这种ifn γ刺激的T-bet表达依赖于通过JAK2和信号转导及转录激活因子1 （STAT1）的信号传导，并激活T-bet依赖的DNA结合活性。T-bet的表达刺激IFNγ刺激的IFNγ表达、分泌和启动子活性，同时抑制IFNγ刺激的趋化因子的释放，包括单核细胞趋化蛋白(MCP)-1/CCL2，受激活正常t表达和分泌(RANTES)/CCL5和eotaxin/CCL11的调节。这伴随着趋化因子受体CCR3、IL12Rβ2和TNFα表达的变化。T-bet的表达也会减少ASMC对血清和PDGF的趋化迁移，从而导致气道增生。这些结果首次确定了T-bet在肺结构细胞中的表达和活性，并可能为炎性气道疾病的治疗靶点提供新的见解。
An inappropriate balance between T-helper (Th)1 and Th2 cytokine production underlies inflammatory changes that result in airway disease. Expression of the T-box transcription factor T-bet regulates differentiation of Th cells and production of Th1 cytokines, particularly IFNγ. T-bet-deficient mice develop airway hyperreactivity, undergo airway remodeling, and exhibit defects in IFNγ production while overproducing Th2 cytokines. T-bet is also reduced in the airways of asthmatic patients, suggesting loss of T-bet expression or activity promotes development of inflammatory airway disease. We present novel data demonstrating T-bet expression is induced in human airway smooth muscle cells (ASMC) by IFNγ. This IFNγ-stimulated expression of T-bet is dependent on signaling through JAK2 and signal transducers and activators of transcription 1 (STAT1) and activates T-bet-dependent DNA binding activity. Expression of T-bet stimulates IFNγ-stimulated IFNγ expression, secretion, and promoter activity, while inhibiting IFNγ-stimulated release of chemokines including monocyte chemoattractant protein (MCP)-1/CCL2, regulated on activation normal T-expressed and secreted (RANTES)/CCL5, and eotaxin/CCL11. This is accompanied by changes in expression of the chemokine receptors CCR3 and IL12Rβ2 and TNFα. T-bet expression also reduces chemotactic migration of ASMC in response to serum and PDGF, which contributes to airway hyperplasia. These results are the first to identify T-bet expression and activity in a structural cell of the lung and may provide new insights into therapeutic targets for inflammatory airway disease.