Knockdown of GRP78 promotes apoptosis in pancreatic acinar cells and attenuates the severity of cerulein and LPS induced pancreatic inflammation.
Knockdown of GRP78 promotes apoptosis in pancreatic acinar cells and attenuates the severity of cerulein and LPS induced pancreatic inflammation.
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GRP78 的敲低促进胰腺腺泡细胞凋亡并减轻雨蛙蛋白和 LPS 诱导的胰腺炎症的严重程度
DOI：
10.1371/journal.pone.0092389
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Liu Y;Yang L;Chen KL;Zhou B;Yan H;Zhou ZG;Li Y
急性胰腺炎（acute pancreatitis，AP）是一种以炎症和实质细胞死亡为特征的潜在致死性疾病，AP的严重程度与坏死直接相关，与凋亡呈负相关。然而，AP中调节细胞死亡的机制仍不清楚。内质网（ER）伴侣蛋白GRP 78具有抗凋亡特性，除了调节ER应激反应。本研究采用RNA干扰（RNA interference，RNAi）技术探讨GRP 78在AP过程中对细胞凋亡的调控作用。用雨蛙肽或雨蛙肽加脂多糖（LPS）处理AR 42 J细胞，成功地建立了AP的体外模型。蛙皮素加LPS处理组胰腺炎症反应明显加重，细胞凋亡明显减少。此外，GRP 78表达的敲低显着促进胰腺腺泡细胞的凋亡和减少坏死。这是通过增强半胱天冬酶的激活和抑制X连锁凋亡抑制蛋白（XIAP）以及受体相互作用蛋白激酶-1（RIPK 1）的活性来实现的，RIPK 1是坏死的关键介质。这减轻了胰腺炎症的严重程度，特别是在雨蛙肽加LPS治疗后。总之，这些发现表明GRP 78在AP期间调节细胞死亡反应中起抗凋亡作用。因此，GRP 78是AP潜在的治疗靶点。
Acute pancreatitis (AP) is a potentially lethal disease characterized by inflammation and parenchymal cell death; also, the severity of AP correlates directly with necrosis and inversely with apoptosis. However, mechanisms of regulating cell death in AP remain unclear. The endoplasmic reticulum (ER) chaperone protein GRP78 has anti-apoptotic properties, in addition to modulating ER stress responses. This study used RNA interference (RNAi) approach to investigate the potential role of GRP78 in regulating apoptosis during AP. In vitro models of AP were successfully developed by treating AR42J cells with cerulein or cerulein plus lipoplysaccharide (LPS). There was more pancreatic inflammation and less apoptosis with the cerulein plus LPS treatment. Furthermore, knockdown of GRP78 expression markedly promoted apoptosis and reduced necrosis in pancreatic acinar cells. This was accomplished by enhancing the activation of caspases and inhibiting the activity of X-linked inhibitor of apoptosis protein (XIAP), as well as a receptor interacting protein kinase-1(RIPK1), which is a key mediator of necrosis. This attenuated the severity of pancreatic inflammation, especially after cerulein plus LPS treatment. In conclusion, these findings indicate that GRP78 plays an anti-apoptotic role in regulating the cell death response during AP. Therefore, GRP78 is a potential therapeutic target for AP.
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影响因子：
64.5
作者：
Du, CY;Fang, M;Wang, XD
通讯作者：
Wang, XD
影响因子：
11.2
作者：
Fu, Yong;Li, Jianze;Lee, Amy S.
通讯作者：
Lee, Amy S.
影响因子：
5.4
作者：
Dull, T;Zufferey, R;Naldini, L
通讯作者：
Naldini, L
DOI：
10.1152/ajpgi.00471.2005
发表时间：
2006-08-01
影响因子：
4.5
作者：
Kubisch, Constanze H.;Sans, Maria Dolors;Logsdon, Craig D.
通讯作者：
Logsdon, Craig D.
影响因子：
4.8
作者：
Lee, AS
通讯作者：
Lee, AS