Yuan Kai, Zhang Xue, Lv Lei, Zhang Jiwei, Liang Wei, Wang Peng
Department of Vascular Surgery, South Campus, Ren ji Hospital, School of Medicine, Shanghai Jiao Tong University, China.
Department of Vascular Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, China.
Int Immunopharmacol. 2016 Nov;40:339-346. doi: 10.1016/j.intimp.2016.09.011. Epub 2016 Sep 24.
Treatment of acetaminophen (APAP) in overdose can cause a potentially serious and fatal liver injury. MicroRNA-155 (miR-155), a multifunctional microRNA, is known to mediate inflammatory responses via regulating various target genes. In this study, we aimed to study the role of miR-155 in APAP-induced liver injury, using miR-155-/- mice and miR-155 in vivo intervention. We noted that miR-155 expression was significantly increased in liver and blood after APAP treatment. Knockout of miR-155 deteriorated APAP-induced liver damage, with the elevated serum levels of AST and ALT. The levels of various inflammatory mediators, such as TNF-α and IL-6, were markedly augmented in livers in the absence of miR-155. Moreover, miR-155 deficiency aberrantly activated NF-kappa-B signaling via enhancing p65 and IKKε expression. Finally, in vivo administration of miR-155 agomir attenuated APAP-induced liver damage, reduced the serum levels of AST and ALT, and dampened the NF-kB signaling. In conclusion, our data demonstrated that miR-155 protects the mice against APAP-induced liver damage via mediating NF-KB signaling pathway, suggesting that miR-155 might be a potential pharmaceutic target for treatment of APAP-induced liver inflammation.
对乙酰氨基酚（APAP）过量服用的治疗可能会导致潜在的严重致命性肝损伤。微小RNA-155（miR-155）是一种多功能微小RNA，已知其通过调节各种靶基因来介导炎症反应。在本研究中，我们旨在利用miR-155基因敲除小鼠和miR-155体内干预来研究miR-155在APAP诱导的肝损伤中的作用。我们注意到，APAP治疗后肝脏和血液中的miR-155表达显著增加。敲除miR-155会使APAP诱导的肝损伤恶化，血清天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）水平升高。在缺乏miR-155的肝脏中，各种炎症介质如肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）的水平显著升高。此外，miR-155缺乏通过增强p65和IKKε的表达异常激活核因子-κB（NF-κB）信号通路。最后，体内给予miR-155激动剂可减轻APAP诱导的肝损伤，降低血清AST和ALT水平，并抑制NF-κB信号通路。总之，我们的数据表明，miR-155通过介导NF-κB信号通路保护小鼠免受APAP诱导的肝损伤，提示miR-155可能是治疗APAP诱导的肝脏炎症的潜在药物靶点。
