Cell death in pancreatitis - Caspases protect from necrotizing pancreatitis
Cell death in pancreatitis - Caspases protect from necrotizing pancreatitis
复制标题
DOI：
10.1074/jbc.m511276200
复制
发表时间：
2006-02-10
影响因子：
4.8
通讯作者：
Gukovskaya, AS
中科院分区：
文献类型：
--
作者：
Mareninova, OA;Sung, KF;Gukovskaya, AS
胰腺炎细胞死亡的机制尚不清楚。实质坏死是胰腺炎的主要并发症；此外，实验性胰腺炎的严重程度与坏死呈正相关，与细胞凋亡呈负相关。因此，将死亡反应从坏死转变为细胞凋亡可能具有治疗价值。为了确定胰腺炎的细胞死亡途径和坏死/凋亡转换的可能性，我们利用了高凋亡低坏死大鼠模型和低凋亡高坏死小鼠模型的差异。我们发现在cerulein胰腺炎大鼠中caspases被极大地激活，而在小鼠中则没有。内源性caspase抑制剂X-linked inhibitor of apoptosis protein （XIAP）在大鼠体内完全降解，但在小鼠模型中保持完整。此外，在小鼠模型中，用栓塞素抑制XIAP可触发caspase激活，提示XIAP参与胰腺炎caspase阻断。Caspase抑制剂可减少大鼠模型中的细胞凋亡并显著刺激坏死，使胰腺炎参数恶化。相反，在小鼠模型中，用栓塞诱导caspase可刺激细胞凋亡，减少坏死。因此，半胱天冬酶不仅介导了胰腺炎的细胞凋亡，而且还保护了胰腺炎的坏死。一种保护机制是通过受体相互作用蛋白（RIP）的降解，RIP是“程序性”坏死的关键介质。我们发现RIP在大鼠中被切割（即失活），而在小鼠模型中没有。Caspase抑制恢复RIP水平；相反，caspase与栓塞诱导可触发RIP裂解。我们的研究结果表明caspases， XIAP和RIP在胰腺炎细胞死亡的调控中起关键作用。操纵这些信号来改变死亡反应的模式是治疗胰腺炎的一种治疗策略。
Mechanisms of cell death in pancreatitis remain unknown. Parenchymal necrosis is a major complication of pancreatitis; also, the severity of experimental pancreatitis correlates directly with necrosis and inversely with apoptosis. Thus, shifting death responses from necrosis to apoptosis may have a therapeutic value. To determine cell death pathways in pancreatitis and the possibility of necrosis/apoptosis switch, we utilized the differences between the rat model of cerulein pancreatitis, with relatively high apoptosis and low necrosis, and the mouse model, with little apoptosis and high necrosis. We found that caspases were greatly activated during cerulein pancreatitis in the rat but not mouse. Endogenous caspase inhibitor X-linked inhibitor of apoptosis protein (XIAP) underwent complete degradation in the rat but remained intact in the mouse model. Furthermore, XIAP inhibition with embelin triggered caspase activation in the mouse model, implicating XIAP in caspase blockade in pancreatitis. Caspase inhibitors decreased apoptosis and markedly stimulated necrosis in the rat model, worsening pancreatitis parameters. Conversely, caspase induction with embelin stimulated apoptosis and decreased necrosis in mouse model. Thus, caspases not only mediate apoptosis but also protect from necrosis in pancreatitis. One protective mechanism is through degradation of receptor-interacting protein (RIP), a key mediator of "programmed" necrosis. We found that RIP was cleaved (i.e. inactivated) in the rat but not the mouse model. Caspase inhibition restored RIP levels; conversely, caspase induction with embelin triggered RIP cleavage. Our results indicate key roles for caspases, XIAP, and RIP in the regulation of cell death in pancreatitis. Manipulating these signals to change the pattern of death responses presents a therapeutic strategy for treatment of pancreatitis.