Acute pancreatitis induces FasL gene expression and apoptosis in the liver
Acute pancreatitis induces FasL gene expression and apoptosis in the liver
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DOI：
10.1016/j.jss.2004.05.019
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发表时间：
2004-12-01
影响因子：
2.2
通讯作者：
Murr, MM
中科院分区：
文献类型：
--
作者：
Gallagher, SF;Yang, J;Murr, MM
背景。肝损伤是急性胰腺炎的重要预后指标。我们之前证明了Kupffer细胞来源的细胞因子介导肝损伤。在这项工作中，我们试图表征Fas配体（FasL）在急性胰腺炎肝损伤中的作用。用丙核蛋白诱导小鼠急性胰腺炎；测定血清FasL、AST、ALT、肝脏FasL、p38-MAPK、caspase-3。用弹性蛋白酶（1 U/ml）模拟急性胰腺炎，测定大鼠Kupffer细胞中FasL mRNA、蛋白及其受体（Fas）的含量。流式细胞术检测细胞凋亡。cerulein诱导的胰腺炎增加了血清AST、ALT和FasL，上调了肝脏FasL（1315 +/- 111比310 +/- 164 pg/ml， P = 0.002比假手术），诱导p38-MAPK磷酸化（P < 0.01比假手术）和caspase-3裂解（P < 0.04比假手术）；经Kupffer细胞抑制剂钆预处理后，所有细胞均减弱（P < 0.003）。在体外，弹性酶诱导Kupffer细胞FasL蛋白的时间依赖性增加（FasL = 404 - 94比170 +/- 40，P = 0.02，与对照组相比），FasL mRNA增加100倍，Fas （FasL受体）上调。钆。显著降低了弹性酶诱导的FasL和FasL mRNA的升高（FasL = 230 20比404 94，P = 0.01，相对于弹性酶），但对Fas影响不大。此外，弹性酶激活的Kupffer细胞培养基诱导肝细胞凋亡（29 +/- 1比16% +/- 1%，与对照组相比，P < 0.001）。急性胰腺炎通过上调FasL、p38-MAPK和caspase-3诱导肝损伤和肝细胞死亡。Fas在Kupffer细胞中上调，表明FasL可能通过诱导其起源细胞死亡来自动调节其产生。操纵库普弗细胞和肝细胞之间相互作用的能力可能具有重要的治疗意义。(C) 2004爱思唯尔公司版权所有。
Background. Liver injury is an important prognostic indicator in acute pancreatitis. We previously demonstrated that Kupffer cell-derived cytokines mediate liver injury. In this work, we sought to characterize the role of Fas Ligand (FasL) in liver injury during acute pancreatitis.Methods. Acute pancreatitis was induced in mice using cerulein; serum FasL, AST, ALT, liver FasL, p38-MAPK, and caspase-3 were measured. FasL mRNA and protein and its receptor (Fas) were determined in rat Kupffer cells treated with elastase (1 U/ml) to mimic acute pancreatitis. Apoptosis was measured by flow cytometry.Results. Cerulein-induced pancreatitis increased serum AST, ALT, and FasL and up-regulated liver FasL (1315 +/- 111 versus 310 +/- 164 pg/ml, P = 0.002 versus sham), while inducing p38-MAPK phosphorylation (P < 0.01 versus sham) and cleavage of caspase-3 (P < 0.04 versus sham); all were attenuated by pretreatment with the Kupffer cell inhibitor, gadolinium (all P < 0.003). In vitro, elastase induced a time-dependent increase in Kupffer cell FasL protein (FasL = 404 94 versus 170 +/- 40, P = 0.02, versus control), a 100-fold increase in FasL mRNA, and up-regulated Fas (FasL receptor). Gadolinium. significantly attenuated the elastase-induced increase in FasL and FasL mRNA (FasL = 230 20 versus 404 94, P = 0.01, versus elastase) but had little effect on Fas. Additionally, elastase-primed Kupffer cell media induced apoptosis in hepatocytes (29 +/- 1 versus 16% +/- 1%; versus control, P < 0.001).Conclusions. Acute pancreatitis induces liver injury and hepatocyte death while up-regulating FasL, p38-MAPK, and caspase-3. Fas is up-regulated within Kupffer cells, suggesting that FasL may autoregulate its production by inducing its originator-cell death. The ability to manipulate interactions between Kupffer cells and hepatocytes may have important therapeutic implications. (C) 2004 Elsevier Inc. All rights reserved.