Curtale Graziella, Renzi Tiziana A, Drufuca Lorenzo, Rubino Marcello, Locati Massimo
Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy.
Humanitas Clinical and Research Center, Rozzano, Italy.
Eur J Immunol. 2017 Dec;47(12):2080-2089. doi: 10.1002/eji.201747044. Epub 2017 Aug 31.
Endotoxin tolerance assures proper regulation of the TLR4 signaling pathway and avoids uncontrolled inflammation, limiting tissue damage and endotoxin shock development. Though underlying molecular mechanisms are still undefined, evidence indicates the involvement of microRNAs, which represent a new layer of regulation of inflammatory pathways. Here, we report that LPS and other inflammatory stimuli repress miR-511-5p expression in human monocytes, while anti-inflammatory stimuli, such as TGF-β and glucocorticoids, have the opposite effect. MiR-511-5p levels selectively influenced cell activation when endotoxin was used, while biological activity of other TLR agonists was unaffected. Consistent with this, TLR4 was validated as the miR-511-5p direct target responsible for glucocorticoids- and TGF-β-mediated inhibition of pro-inflammatory cytokines production observed in endotoxin tolerant monocytes. MiR-511-5p thus acts as an intracellular mediator of glucocorticoids and TGF-β for the induction of endotoxin tolerance in human monocytes.
内毒素耐受性确保了Toll样受体4（TLR4）信号通路的正常调节，并避免不受控制的炎症反应，限制组织损伤和内毒素休克的发生。尽管潜在的分子机制仍不明确，但有证据表明微小RNA（microRNA）参与其中，这代表了炎症通路调节的一个新层面。在此，我们报告脂多糖（LPS）和其他炎症刺激会抑制人单核细胞中miR-511-5p的表达，而抗炎刺激，如转化生长因子-β（TGF-β）和糖皮质激素，则具有相反的作用。当使用内毒素时，miR-511-5p水平选择性地影响细胞活化，而其他TLR激动剂的生物学活性不受影响。与此一致，TLR4被确认为miR-511-5p的直接靶点，它介导了在对内毒素耐受的单核细胞中观察到的糖皮质激素和TGF-β对促炎细胞因子产生的抑制作用。因此，miR-511-5p作为糖皮质激素和TGF-β的细胞内介质，可诱导人单核细胞产生内毒素耐受性。
