NFκB inhibition decreases hepatocyte proliferation but does not alter apoptosis in obstructive jaundice
NFκB inhibition decreases hepatocyte proliferation but does not alter apoptosis in obstructive jaundice
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DOI：
10.1016/s0022-4804(03)00280-4
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发表时间：
2003-10-01
影响因子：
2.2
通讯作者：
Behrns, KE
中科院分区：
文献类型：
--
作者：
Bird, MA;Black, D;Behrns, KE
导言。胆汁淤积症激活核因子kappaB(NFkappaB)，核因子kappaB参与肝细胞增殖和凋亡，这取决于细胞微环境。我们假设在肝外胆道梗阻的大鼠模型中，抑制NFkappaB会减少肝细胞的增殖并增强肝细胞的凋亡。目的：确定抑制NFkappaB是否同时抑制梗阻性黄疸肝细胞的增殖和增加细胞的凋亡。雄性SD大鼠接受假手术或胆管结扎(BDL)联合门静脉注射赋形剂或携带对照荧光素酶或IkappaB超抑制子(AdIkappaBSR)转基因的6×10(9)粒腺病毒。分别于假手术后3、5、7d取材，免疫组织化学方法检测增殖细胞核抗原和dUTP缺口末端标记法检测肝细胞DNA合成和细胞凋亡。血清总胆红素和苏木素升高以及肝切片伊红染色证实了胆汁淤积动物。Western印迹分析表明，IkappaBSR蛋白仅在AdIkappaBSR感染的动物中表达。在第7天，与携带对照荧光素酶的腺病毒和赋形剂处理的对照相比，抑制NFkappaB减少了BDL大鼠肝细胞DNA的合成。与假手术组相比，BDL赋形剂治疗组肝细胞凋亡率增加，但抑制NFkappaB不改变BDL组肝细胞凋亡。在梗阻性胆汁淤积症中，NFkappaB是肝细胞增殖所必需的，但不能促进细胞凋亡。(C)2003 Elsevier Inc.保留所有权利。
Introduction. Cholestasis activates nuclear factor kappa B (NFkappaB), which is involved in both hepatocyte proliferation and apoptosis, depending on the cellular microenvironment. We hypothesized that NFkappaB inhibition would decrease hepatocyte proliferation and potentiate hepatocyte apoptosis in a rat model of extrahepatic biliary obstruction.Aim. To determine if NFkappaB inhibition concomitantly decreases hepatocyte proliferation and increases apoptosis in obstructive jaundice.Materials and methods. Male Sprague-Dawley rats underwent either sham operation or bile-duct ligation (BDL) combined with portal vein injection of vehicle or 6 x 10(9) particles of an adenovirus carrying either the control luciferase or the IkappaB super-repressor (AdIkappaBSR) transgenes. Liver was harvested 3, 5, and 7 days after sham operation or BDL, and immunohistochemistry for proliferating cell nuclear antigen and terminal dUTP nick end-labeling was performed for detection of DNA synthesis and apoptosis, respectively.Results. Increased serum total bilirubin and hematoxylin and eosin-stained liver sections confirmed cholestasis in BDL animals. Western blot analysis demonstrated IkappaBSR protein expression in AdIkappaBSR-infected animals only. At day 7, NFkappaB inhibition decreased hepatocyte DNA synthesis in BDL rats compared to both adenovirus carrying the control luciferase and vehicle-treated controls. Apoptosis was increased in BDL vehicle-treated animals compared to sham-operation animals, but NFkappaB inhibition did not alter hepatocyte apoptosis in the BDL group.Conclusion. In obstructive cholestasis, NFkappaB is required for hepatocyte proliferation, but does not augment apoptosis. (C) 2003 Elsevier Inc. All rights reserved.