IL-9 通过 STAT3 信号通路诱导人气道平滑肌细胞中 CCL11 的表达。

BACKGROUND

Previous findings support the concept that IL-9 may play a significant role in mediating both pro-inflammatory and changes in airway responsiveness that characterizes the atopic asthmatic state. We previously demonstrated that human airway smooth muscle (ASM) cells express a functional IL-9R that mediate CCL11 expression. However, the signaling pathway governing this effect is not well understood.

METHODOLOGY/PRINCIPAL FINDINGS: In this study, we showed that IL-9 mediated CCL11 expression in ASM cells does not rely on STAT6 or STAT5 but on STAT3 pathway. IL-9 induced rapid STAT3 activation in primary ASM cells that was not observed in case of STAT6 or STAT5. STAT3 binding to CCL11 promoter was also observed in vivo upon IL-9 stimulation of ASM cells. Disruption of STAT3 activity with SH2 domain binding inhibitory peptide results in significant reduction of IL-9 mediated CCL11 promoter activity. DN STAT3beta over-expression in ASM cells, but not Ser 727 STAT3 or STAT6 DN, abolishes IL-9 mediated CCL11 promoter activity. Finally, STAT3 but not STAT6 silenced ASM cells showed significant reduction in IL-9 mediated CCL11 promoter activity and mRNA expression.

CONCLUSION/SIGNIFICANCE: Taken together, our results indicate that IL-9 mediated CCL11 via STAT3 signalling pathway may play a crucial role in airway inflammatory responses.

背景

先前的研究结果支持这样一种观点，即白细胞介素 9（IL-9）可能在介导促炎反应和气道反应性变化方面发挥重要作用，而这些变化是特应性哮喘状态的特征。我们之前的研究表明，人气道平滑肌（ASM）细胞表达一种功能性的 IL-9R，介导 CCL11 的表达。然而，调节这种效应的信号通路尚不清楚。

方法/主要发现：在这项研究中，我们表明，IL-9 介导的 ASM 细胞中的 CCL11 表达不依赖于 STAT6 或 STAT5，而是依赖于 STAT3 途径。IL-9 在原代 ASM 细胞中诱导快速的 STAT3 激活，但在 STAT6 或 STAT5 中未观察到这种情况。在 IL-9 刺激 ASM 细胞后，也观察到 STAT3 结合到 CCL11 启动子上。用 SH2 结构域结合抑制肽阻断 STAT3 活性会导致 IL-9 介导的 CCL11 启动子活性显著降低。在 ASM 细胞中过表达 DN STAT3beta，但不是 Ser 727 STAT3 或 STAT6 DN，会消除 IL-9 介导的 CCL11 启动子活性。最后，STAT3 沉默而不是 STAT6 沉默的 ASM 细胞显示出 IL-9 介导的 CCL11 启动子活性和 mRNA 表达显著降低。

结论/意义：综上所述，我们的研究结果表明，IL-9 通过 STAT3 信号通路介导的 CCL11 可能在气道炎症反应中发挥关键作用。