Tomar Sunil, Zumbrun Elizabeth E, Nagarkatti Mitzi, Nagarkatti Prakash S
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina (S.T., E.E.Z., M.N., P.S.N.); and Wm. Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, South Carolina (M.N.).
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, South Carolina (S.T., E.E.Z., M.N., P.S.N.); and Wm. Jennings Bryan Dorn Veterans Affairs Medical Center, Columbia, South Carolina (M.N.)
J Pharmacol Exp Ther. 2015 May;353(2):369-79. doi: 10.1124/jpet.114.220368. Epub 2015 Mar 6.
Acute liver failure (ALF) is a potentially life-threatening disorder without any effective treatment strategies. d-Galactosamine (GalN)/lipopolysaccharide (LPS)-induced ALF is a widely used animal model to identify novel hepato-protective agents. In the present study, we investigated the potential of a cannabinoid receptor 2 (CB2) agonist, JWH-133 [(6aR,10aR)-3-(1,1-dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran], in the amelioration of GalN/LPS-induced ALF. JWH-133 treatment protected the mice from ALF-associated mortality, mitigated alanine transaminase and proinflammatory cytokines, suppressed histopathological and apoptotic liver damage, and reduced liver infiltration of mononuclear cells (MNCs). Furthermore, JWH-133 pretreatment of M1/M2-polarized macrophages significantly increased the secretion of anti-inflammatory cytokine interleukin-10 (IL-10) in M1 macrophages and potentiated the expression of M2 markers in M2-polarized macrophages. In vivo, JWH-133 treatment also suppressed ALF-triggered expression of M1 markers in liver MNCs, while increasing the expression of M2 markers such as Arg1 and IL-10. microRNA (miR) microarray analysis revealed that JWH-133 treatment altered the expression of only a few miRs in the liver MNCs. Gene ontology analysis of the targets of miRs suggested that Toll-like receptor (TLR) signaling was among the most significantly targeted cellular pathways. Among the altered miRs, miR-145 was found to be the most significantly decreased. This finding correlated with concurrent upregulated expression of its predicted target gene, interleukin-1 receptor-associated kinase 3, a negative regulator of TLR4 signaling. Together, these data are the first to demonstrate that CB2 activation attenuates GalN/LPS-induced ALF by inducing an M1 to M2 shift in macrophages and by regulating the expression of unique miRs that target key molecules involved in the TLR4 pathway.
急性肝衰竭（ALF）是一种潜在的危及生命的疾病，目前尚无有效的治疗策略。d-半乳糖胺（GalN）/脂多糖（LPS）诱导的ALF是一种广泛用于鉴定新型肝保护剂的动物模型。在本研究中，我们研究了大麻素受体2（CB2）激动剂JWH-133[（6aR，10aR）-3-（1,1-二甲基丁基）-6a，7，10，10a-四氢-6，6，9-三甲基-6H-二苯并[b，d]吡喃]改善GalN/LPS诱导的ALF的潜力。JWH-133治疗可保护小鼠免于ALF相关的死亡，减轻丙氨酸转氨酶和促炎细胞因子水平，抑制组织病理学和凋亡性肝损伤，并减少肝脏单核细胞（MNC）浸润。此外，JWH-133对M1/M2极化巨噬细胞的预处理显著增加了M1巨噬细胞中抗炎细胞因子白细胞介素-10（IL-10）的分泌，并增强了M2极化巨噬细胞中M2标志物的表达。在体内，JWH-133治疗还抑制了ALF触发的肝脏MNC中M1标志物的表达，同时增加了Arg1和IL-10等M2标志物的表达。微小RNA（miR）微阵列分析显示，JWH-133治疗仅改变了肝脏MNC中少数miR的表达。对miR靶标的基因本体分析表明，Toll样受体（TLR）信号通路是最显著的靶向细胞通路之一。在改变的miR中，发现miR-145显著降低。这一发现与其预测靶基因白细胞介素-1受体相关激酶3（TLR4信号的负调节因子）的同时上调表达相关。总之，这些数据首次证明，CB2激活通过诱导巨噬细胞从M1向M2转变以及调节靶向TLR4通路中关键分子的独特miR的表达，减轻GalN/LPS诱导的ALF。
