Section of Airways Disease, National Heart & Lung Institute, Imperial College London, UK.
J Inflamm (Lond). 2010 Jul 16;7:33. doi: 10.1186/1476-9255-7-33.
The key co-repressor complex components HDAC-2, Mi-2alpha/beta and mSin3a are all critical to the regulation of gene transcription. HDAC-2 function is impaired by oxidative stress in a PI3Kdelta dependant manner which may be involved in the chronic glucocorticoid insensitive inflammation in the lungs of COPD patients. However, the impact of cigarette smoke exposure on the expression of mSin3a and Mi2alpha/beta and their role in glucocorticoid responsiveness is unknown.
Wild type, PI3Kgamma knock-out (PI3Kgamma-/-) and PI3K kinase dead knock-in (PI3KdeltaD910/A910) transgenic mice were exposed to cigarette smoke for 3 days and the expression levels of the co-repressor complex components HDAC-2, mSin3a, Mi-2alpha and Mi-2beta and HDAC-2 activity in the lungs were assessed.
Cigarette smoke exposure impaired glucocorticoid function and reduced HDAC-2 activity which was protected in the PI3KdeltaD910/A910 mice. Both mSin3a and Mi-2alpha protein expression was reduced in smoke-exposed mice. Budesonide alone protected mSin3a protein expression with no additional effect seen with abrogation of PI3Kgamma/delta activity, however Mi-2alpha, but not Mi-2beta, expression was protected in both PI3KdeltaD910/A910 and PI3Kgamma-/- budesonide-treated smoke-exposed mice. The restoration of glucocorticoid function coincided with the protection of both HDAC activity and mSin3a and Mi-2alpha protein expression.
Cigarette smoke exposure induced glucocorticoid insensitivity and alters co-repressor activity and expression which is prevented by blockade of PI3K signaling with glucocorticoid treatment. Inhibition of PI3Kdelta signalling in combination with glucocorticoid treatment may therefore provide a therapeutic strategy for restoring oxidant-induced glucocortiocid unresponsiveness.
关键的共抑制复合物组件 HDAC-2、Mi-2alpha/beta 和 mSin3a 对于基因转录的调节都至关重要。HDAC-2 的功能受到 PI3Kdelta 依赖性氧化应激的损害，这可能与 COPD 患者肺部慢性糖皮质激素不敏感炎症有关。然而，香烟烟雾暴露对 mSin3a 和 Mi2alpha/beta 的表达的影响及其在糖皮质激素反应性中的作用尚不清楚。
野生型、PI3Kgamma 敲除（PI3Kgamma-/-）和 PI3K 激酶失活敲入（PI3KdeltaD910/A910）转基因小鼠暴露于香烟烟雾中 3 天，评估共抑制复合物组件 HDAC-2、mSin3a、Mi-2alpha 和 Mi-2beta 的表达水平以及肺部 HDAC-2 活性。
香烟烟雾暴露损害了糖皮质激素功能并降低了 HDAC-2 活性，而在 PI3KdeltaD910/A910 小鼠中则得到了保护。暴露于烟雾的小鼠中 mSin3a 和 Mi-2alpha 蛋白表达减少。布地奈德单独保护 mSin3a 蛋白表达，而阻断 PI3Kgamma/delta 活性则没有额外的效果，然而 Mi-2alpha，但不是 Mi-2beta，在 PI3KdeltaD910/A910 和 PI3Kgamma-/-布地奈德处理的烟雾暴露小鼠中都得到了保护。糖皮质激素功能的恢复与 HDAC 活性以及 mSin3a 和 Mi-2alpha 蛋白表达的保护同时发生。
香烟烟雾暴露诱导糖皮质激素不敏感，并改变共抑制物的活性和表达，而糖皮质激素治疗可防止 PI3K 信号转导的抑制。因此，抑制 PI3Kdelta 信号通路与糖皮质激素治疗相结合可能为恢复氧化应激诱导的糖皮质激素不反应提供一种治疗策略。
