Deletion Of XIAP reduces the severity of acute pancreatitis via regulation of cell death and nuclear factor-κB activity.
Deletion Of XIAP reduces the severity of acute pancreatitis via regulation of cell death and nuclear factor-κB activity.
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XIAP 缺失通过调节细胞死亡和核因子-κ B 活性降低急性胰腺炎的严重程度
DOI：
10.1038/cddis.2017.70
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发表时间：
2017-03-16
影响因子：
9
通讯作者：
Zhou ZG
中科院分区：
文献类型：
--
作者：
Liu Y;Chen XD;Yu J;Chi JL;Long FW;Yang HW;Chen KL;Lv ZY;Zhou B;Peng ZH;Sun XF;Li Y;Zhou ZG
重症急性胰腺炎（SAP）仍然是一个临床挑战，不仅是因为其高死亡率，而且从急性胰腺炎（AP）到SAP的炎症进展不受控制。细胞死亡（包括凋亡和坏死）是AP的重要病理过程，胰腺炎的严重程度与坏死直接相关，与凋亡呈负相关。因此，调控细胞从坏死到凋亡的死亡过程可能具有实用的治疗价值。X连锁凋亡抑制蛋白（XIAP）是凋亡抑制蛋白（IAP）家族中最具代表性的成员，但其在AP中的功能尚不清楚。在本研究中，我们研究了XIAP在急性胰腺炎细胞死亡和炎症调节中的潜在作用。通过在野生型或XIAP缺陷型小鼠中施用雨蛙肽与或不与脂多糖（LPS）或通过施用L-精氨酸诱导体内胰腺炎模型，并且通过在XIAP抑制后在AR 42 J细胞系中施用雨蛙肽+LPS诱导离体模型。根据血清淀粉酶活性和组织学分级判断急性胰腺炎的严重程度。检测XIAP缺失对细胞凋亡、坏死及炎症反应的影响。Western blot检测Caspase活性、核因子-κB（NF-κB）活性和受体相互作用蛋白激酶1（RIP 1）降解。XIAP基因缺失可导致胰腺腺泡细胞淀粉酶活性降低，NF-κB活性降低，TNF-α和IL-6释放减少，caspase活性增加，RIP 1降解增加，胰腺腺泡细胞凋亡增加，坏死减少，胰腺炎严重程度减轻。我们的研究结果表明，XIAP的缺失将细胞死亡从坏死转变为凋亡，并降低炎症反应，有效地减轻AP/SAP的严重程度。XIAP在细胞死亡和炎症中的关键作用表明，抑制XIAP代表了治疗急性胰腺炎的潜在治疗策略。
Severe acute pancreatitis (SAP) still remains a clinical challenge, not only for its high mortality but the uncontrolled inflammatory progression from acute pancreatitis (AP) to SAP. Cell death, including apoptosis and necrosis are critical pathology of AP, since the severity of pancreatitis correlates directly with necrosis and inversely with apoptosis Therefore, regulation of cell death from necrosis to apoptosis may have practicably therapeutic value. X-linked inhibitor of apoptosis protein (XIAP) is the best characterized member of the inhibitor of apoptosis proteins (IAP) family, but its function in AP remains unclear. In the present study, we investigated the potential role of XIAP in regulation of cell death and inflammation during acute pancreatitis. The in vivo pancreatitis model was induced by the administration of cerulein with or without lipopolysaccharide (LPS) or by the administration of l-arginine in wild-type or XIAP-deficient mice, and ex vivo model was induced by the administration of cerulein+LPS in AR42J cell line following XIAP inhibition. The severity of acute pancreatitis was determined by serum amylase activity and histological grading. XIAP deletion on cell apoptosis, necrosis and inflammatory response were examined. Caspases activities, nuclear factor-κB (NF-κB) activation and receptor-interacting protein kinase1 (RIP1) degradation were assessed by western blot. Deletion of XIAP resulted in the reduction of amylase activity, decrease of NF-κB activation and less release of TNF-α and IL-6, together with increased caspases activities and RIP1 degradation, leading to enhanced apoptosis and reduced necrosis in pancreatic acinar cells and ameliorated the severity of acute pancreatitis. Our results indicate that deletion of XIAP switches cell death away from necrosis to apoptosis and decreases the inflammatory response, effectively attenuating the severity of AP/SAP. The critical role of XIAP in cell death and inflammation suggests that inhibition of XIAP represents a potential therapeutic strategy for the treatment of acute pancreatitis.