Secretagogues differentially activate endoplasmic reticulum stress responses in pancreatic acinar cells
Secretagogues differentially activate endoplasmic reticulum stress responses in pancreatic acinar cells
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DOI：
10.1152/ajpgi.00078.2007
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发表时间：
2007-06-01
影响因子：
4.5
通讯作者：
Logsdon, Craig D.
中科院分区：
文献类型：
--
作者：
Kubisch, Constanze H.;Logsdon, Craig D.
内质网（ER）应激导致错误折叠蛋白在内质网腔中积累，并启动未折叠蛋白反应（UPR）。UPR的组分在胰腺发育中是重要的，并且最近的研究表明UPR在急性胰腺炎的精氨酸模型中被激活。然而，促分泌素对胰腺中UPR组分的影响尚不清楚。本研究的目的是研究不同类型和浓度的促分泌素对腺泡细胞功能和UPR的特定成分的影响。用CCK类似物CCK 8（10 pM - 10 nM）或JMV- 180（10 nM - 10 μ M）或铃蟾肽（1 - 100 nM）刺激大鼠胰腺腺泡。测量UPR的组分，包括伴侣BiP表达、PKR样ER激酶（PERK）磷酸化、X盒结合蛋白1（XBP 1）剪接和CCAAT/增强子结合蛋白同源蛋白（CHOP）表达，以及对淀粉酶分泌和细胞内胰蛋白酶活化的影响。CCK 8产生双相分泌剂量-反应曲线，高浓度增加细胞内活性胰蛋白酶水平。相反，JMV- 180和蛙皮素分泌量-反应曲线为双相，高浓度不增加细胞内胰蛋白酶活性。所有三种促分泌素都增加了BiP水平和XBP 1剪接。然而，只有超生理水平的CCK 8与抑制淀粉酶分泌和胰蛋白酶激活刺激PERK磷酸化和表达的CHOP。CCK 8对UPR组分的影响是快速的，发生在5 - 20分钟内。总之，ER应激反应机制似乎参与胰腺生理和病理生理，未来的努力应该是针对了解这些机制在胰腺中的作用。
Endoplasmic reticulum ( ER) stress leads to the accumulation of misfolded proteins in the ER lumen and initiates the unfolded protein response ( UPR). Components of the UPR are important in pancreatic development, and recent studies have indicated that the UPR is activated in the arginine model of acute pancreatitis. However, the effects of secretagogues on UPR components in the pancreas are unknown. The present study aimed to examine the effects of different types and concentrations of secretagogues on acinar cell function and specific components of the UPR. Rat pancreatic acini were stimulated with the CCK analogs CCK8 ( 10 pM - 10 nM) or JMV- 180 ( 10 nM - 10 mu M) or with bombesin ( 1 - 100 nM). Components of the UPR, including chaperone BiP expression, PKR-like ER kinase ( PERK) phosphorylation, X box- binding protein 1 ( XBP1) splicing, and CCAAT/ enhancer binding protein homologous protein ( CHOP) expression, were measured, as were effects on amylase secretion and intracellular trypsin activation. CCK8 generated a biphasic secretion dose- response curve, and high concentrations increased intracellular active trypsin levels. In contrast, JMV- 180 and bombesin secretion dose- response curves were monophasic, and high concentrations did not increase intracellular trypsin activity. All three secretagogues increased BiP levels and XBP1 splicing. However, only supraphysiological levels of CCK8 associated with inhibited amylase secretion and trypsin activation stimulated PERK phosphorylation and expression of CHOP. The effects of CCK8 on UPR components were rapid, occurring within 5 - 20 min. In conclusion, ER stress response mechanisms appear to be involved in both pancreatic physiology and pathophysiology, and future efforts should be directed at understanding the roles of these mechanisms in the pancreas.