Proteasome inhibition induces hepatic stellate cell apoptosis
Proteasome inhibition induces hepatic stellate cell apoptosis
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DOI：
10.1002/hep.21036
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发表时间：
2006-02-01
期刊：
影响因子：
13.5
通讯作者：
Gores, GJ
中科院分区：
文献类型：
--
作者：
Anan, A;Baskin-Bey, ES;Gores, GJ
诱导肝星状细胞（HSC）凋亡可减轻肝纤维化，因此，诱导HSC细胞死亡的机制具有治疗意义。蛋白酶体抑制剂可诱导转化细胞凋亡，特别是那些依赖核因子κ B （nf - κ B）活化的细胞。由于受刺激的HSC也会触发NF-kappa B活化，因此本研究的目的是确定蛋白酶体抑制剂是否会诱导HSC凋亡。用蛋白酶体抑制剂硼替佐米和MG132处理永生化的人HSC系、LX-2和原代大鼠HSC。两种蛋白酶体抑制剂均诱导HSC凋亡。蛋白酶体抑制NF-kappa B的激活，更重要的是，bay11 -7082触发的HSC凋亡抑制NF-kappa B。活化的HSC存活依赖于NF-kappa B靶基因A1，一个抗凋亡的Bcl-2家族成员，作为siRNA靶向敲低A1诱导的HSC凋亡。相反，蛋白酶体抑制诱导的TRAIL、死亡受体5和Bim的改变与凋亡反应无关。这些发现的相关性在胆管结扎小鼠中得到证实，硼替佐米降低了肝星状细胞活化和纤维化的标志物。总之，蛋白酶体抑制是诱导HSC凋亡和抑制肝纤维化的潜在治疗策略。
Induction of hepatic stellate cell (HSC) apoptosis attenuates hepatic fibrosis, and, therefore, mechanisms to induce HSC cell death are of therapeutic interest. Proteasome inhibitors induce apoptosis in transformed cells, especially those cells dependent upon nuclear factor kappa B (NF-kappa B) activation. Because stimulated HSCs also trigger NF-kappa B activation, the aim of this study was to determine if proteasome inhibitors induce HSC apoptosis. The immortalized human HSC line, LX-2, and primary rat HSCs were treated with the proteasome inhibitors bortezomib and MG132. Both proteasome inhibitors induced HSC apoptosis. Proteasome inhibition blocked NF-kappa B activation and, more importantly, NF-kappa B inhibition by Bay11-7082-triggered HSC apoptosis. Activated HSC survival is dependent upon the NF-kappa B target gene A1, an anti-apoptotic Bcl-2 family member, as siRNA targeted knockdown of A1-induced HSC apoptosis. In contrast, proteasome inhibition-induced alterations in TRAIL, death receptor 5, and Bim could not be implicated in the apoptotic response. The relevance of these findings was confirmed in the bile-duct-ligated mouse where bortezomib reduced hepatic markers of stellate cell activation and fibrosis. In conclusion, proteasome inhibition is a potential therapeutic strategy for inducing HSC apoptosis and inhibiting liver fibrogenesis.