Abstract：
15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) exhibited potential to alleviate liver inflammation in chronic injury but was less studied in acute injury. Acute liver injury was associated with elevated macrophage migration inhibitory factor (MIF) levels in damaged hepatocytes. This study aimed to investigate the regulatory mechanism of hepatocyte-derived MIF by 15d-PGJ2 and its subsequent impact on acute liver injury. In vivo, mouse models were established by carbon tetrachloride (CCl4) intraperitoneal injection, with or without 15d-PGJ2 administration. 15d-PGJ2 treatment reduced the necrotic areas induced by CCl4. In the same mouse model constructed using enhanced green fluorescent protein (EGFP)-labeled bone marrow (BM) chimeric mice, 15d-PGJ2 reduced CCl4 induced BM-derived macrophage (BMM, EGFP+F4/80+) infiltration and inflammatory cytokine expression. Additionally, 15d-PGJ2 down-regulated liver and serum MIF levels; liver MIF expression was positively correlated with BMM percentage and inflammatory cytokine expression. In vitro, 15d-PGJ2 inhibited Mif expression in hepatocytes. In primary hepatocytes, reactive oxygen species inhibitor (NAC) showed no effect on MIF inhibition by 15d-PGJ2; PPARγ inhibitor (GW9662) abolished 15d-PGJ2 suppressed MIF expression and antagonists (troglitazone, ciglitazone) mimicked its function. In Pparg silenced AML12 cells, the suppression of MIF by 15d-PGJ2 was weakened; 15d-PGJ2 promoted PPARγ activation in AML 12 cells and primary hepatocytes. Furthermore, the conditioned medium of recombinant MIF- and lipopolysaccharide-treated AML12 respectively promoted BMM migration and inflammatory cytokine expression. Conditioned medium of 15d-PGJ2- or siMif-treated injured AML12 suppressed these effects. Collectively, 15d-PGJ2 activated PPARγ to suppress MIF expression in injured hepatocytes, reducing BMM infiltration and pro-inflammatory activation, ultimately alleviating acute liver injury.
摘要：
15-脱氧-Δ12,14-前列腺素J2（15d-PGJ2）在慢性损伤中表现出减轻肝脏炎症的潜力，但在急性损伤中的研究较少。急性肝损伤与受损肝细胞中巨噬细胞移动抑制因子（MIF）水平升高有关。本研究旨在探讨15d-PGJ2对肝细胞源性MIF的调控机制及其对急性肝损伤的影响。在体内,采用四氯化碳(CCl4)腹腔注射建立小鼠模型,有或没有15d-PGJ2给药。15d-PGJ2处理减少了CCl4诱导的坏死区域。在使用增强的绿色荧光蛋白（EGFP）标记的骨髓（BM）嵌合小鼠构建的相同小鼠模型中，15d-PGJ2减少CCl4诱导的BM衍生巨噬细胞(BMM，EGFP+F4/80+)浸润和炎性细胞因子表达。此外,15d-PGJ2下调肝脏和血清MIF水平；肝脏MIF表达与BMM百分比和炎性细胞因子表达呈正相关。体外，15d-PGJ2抑制肝细胞中的Mif表达。在原代肝细胞中，活性氧抑制剂（NAC）对15d-PGJ2抑制MIF没有影响；PPARγ抑制剂（GW9662）消除了15d-PGJ2抑制的MIF表达和拮抗剂（曲格列酮，西格列酮）模仿了它的功能。在Pparg沉默的AML12细胞中，15d-PGJ2对MIF的抑制作用减弱；15d-PGJ2促进AML12细胞和原代肝细胞中PPARγ的激活。此外，重组MIF和脂多糖处理的AML12的条件培养基分别促进BMM迁移和炎性细胞因子表达。15d-PGJ2-或siMif处理的损伤AML12的条件培养基抑制了这些作用。总的来说，15d-PGJ2激活PPARγ抑制损伤肝细胞中MIF的表达，减少BMM浸润和促炎激活，最终缓解急性肝损伤。
