Beil Michael, Leser Jürgen, Lutz Manfred P, Gukovskaya Anna, Seufferlein Thomas, Lynch Grit, Pandol Stephen J, Adler Guido
Department of Internal Medicine I, University of Ulm, 89070 Ulm, Germany.
Am J Physiol Gastrointest Liver Physiol. 2002 Mar;282(3):G450-60. doi: 10.1152/ajpgi.00042.2001.
Pancreatic acinar cells depend on the integrity of the cytoskeleton for regulated secretion. Stimulation of isolated rat pancreatic acini with the secretagogue CCK serves as a model for human acute edematous pancreatitis. It induces the breakdown of the actin filament system (F-actin) with the consecutive inhibition of secretion and premature activation of digestive enzymes. However, the mechanisms that regulate F-actin breakdown are largely unknown. Plectin is a versatile cytolinker protein regulating F-actin dynamics in fibroblasts. It was recently demonstrated that plectin is a substrate of caspase 8. In pancreatic acinar cells, plectin strongly colocalizes with apical and basolateral F-actin. Supramaximal secretory stimulation of acini with CCK leads to a rapid redistribution and activation of caspase 8, followed by degradation of plectin that in turn precedes the F-actin breakdown. Inhibition of caspase 8 before CCK hyperstimulation prevents plectin cleavage, stabilizes F-actin morphology, and reverses the inhibition of secretion. Thus we propose that the caspase 8-mediated degradation of plectin represents a critical biochemical event during CCK-induced secretory blockade and cell injury.
胰腺腺泡细胞的调节性分泌依赖于细胞骨架的完整性。用促分泌剂胆囊收缩素（CCK）刺激分离的大鼠胰腺腺泡，可作为人类急性水肿性胰腺炎的模型。它会诱导肌动蛋白丝系统（F-肌动蛋白）的分解，进而抑制分泌并使消化酶过早激活。然而，调节F-肌动蛋白分解的机制在很大程度上尚不清楚。网蛋白是一种多功能的细胞连接蛋白，可调节成纤维细胞中F-肌动蛋白的动态变化。最近有研究表明，网蛋白是半胱天冬酶8的底物。在胰腺腺泡细胞中，网蛋白与顶端和基底外侧的F-肌动蛋白强烈共定位。用CCK对腺泡进行超最大分泌刺激会导致半胱天冬酶8迅速重新分布并激活，随后网蛋白降解，而网蛋白降解又先于F-肌动蛋白分解。在CCK过度刺激之前抑制半胱天冬酶8可防止网蛋白裂解，稳定F-肌动蛋白形态，并逆转分泌抑制。因此，我们认为半胱天冬酶8介导的网蛋白降解是CCK诱导的分泌阻断和细胞损伤过程中的一个关键生化事件。
