Moschos Sterghios A, Williams Andrew E, Perry Mark M, Birrell Mark A, Belvisi Maria G, Lindsay Mark A
Biopharmaceutics Research Group, Airway Diseases Unit, National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
BMC Genomics. 2007 Jul 17;8:240. doi: 10.1186/1471-2164-8-240.
At present, nothing is known of the role of miRNAs in the immune response in vivo despite the fact that inflammation is thought to underlie multiple acute and chronic diseases. In these circumstances, patients are commonly treated with corticosteroids such as dexamethasone.
To address this question, we have examined the differential expression of 104 miRNAs using real-time PCR during the innate immune response in mouse lung following exposure to aerosilised lipopolysaccharide (LPS). Following challenge, we observed rapid and transient increase in both the mean (4.3-fold) and individual levels of miRNA expression (46 miRNAs) which peaked at 3 hrs. Crucially, this increase was correlated with a reduction in the expression of tumour necrosis factor (TNF)-alpha, keratinocyte-derived chemokine (KC) and macrophage inflammatory protein (MIP)-2, suggesting a potential role for miRNAs in the regulation of inflammatory cytokine production. Examination of the individual miRNA expression profiles showed time dependent increases in miR-21, -25, -27b, -100, 140, -142-3p, -181c, 187, -194, -214, -223 and -224. Corticosteroid studies showed that pre-treatment with dexamethasone at concentrations that inhibited TNF-alpha production, had no effect either alone or upon the LPS-induced miRNA expression profile.
We have shown that the LPS-induced innate immune response is associated with widespread, rapid and transient increases in miRNA expression in the mouse lung and we speculate that these changes might be involved in the regulation of the inflammatory response. In contrast, the lack of effect of dexamethasone in either control or challenged animals implies that the actions of glucocorticoids per se are not mediated through changes in miRNAs expression and that LPS-induced increases in miRNA expression are not mediated via classical inflammatory transcription factors.
目前，尽管炎症被认为是多种急慢性疾病的基础，但关于微小RNA（miRNA）在体内免疫反应中的作用尚不清楚。在这种情况下，患者通常使用地塞米松等皮质类固醇进行治疗。
为了解决这个问题，我们在小鼠肺部暴露于雾化脂多糖（LPS）后的天然免疫反应过程中，使用实时聚合酶链反应（PCR）检测了104种miRNA的差异表达。受到刺激后，我们观察到miRNA表达的平均值（4.3倍）和个体水平（46种miRNA）均迅速且短暂增加，在3小时时达到峰值。至关重要的是，这种增加与肿瘤坏死因子（TNF）-α、角质形成细胞衍生趋化因子（KC）和巨噬细胞炎性蛋白（MIP）-2的表达降低相关，这表明miRNA在调节炎性细胞因子产生中可能发挥作用。对个体miRNA表达谱的检测显示，miR-21、-25、-27b、-100、140、-142-3p、-181c、187、-194、-214、-223和-224的表达随时间增加。皮质类固醇研究表明，以抑制TNF-α产生的浓度进行地塞米松预处理，单独使用或对LPS诱导的miRNA表达谱均无影响。
我们已经表明，LPS诱导的天然免疫反应与小鼠肺部miRNA表达的广泛、快速和短暂增加有关，我们推测这些变化可能参与炎症反应的调节。相比之下，地塞米松在对照动物或受刺激动物中均无作用，这意味着糖皮质激素本身的作用不是通过miRNA表达的变化介导的，并且LPS诱导的miRNA表达增加不是通过经典炎性转录因子介导的。
