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原代肝细胞体外培养时Fas/CD95死亡信号从II型向I型转换。

Switch from type II to I Fas/CD95 death signaling on in vitro culturing of primary hepatocytes.

作者信息

Walter Dorothée, Schmich Kathrin, Vogel Sandra, Pick Robert, Kaufmann Thomas, Hochmuth Florian Christoph, Haber Angelika, Neubert Karin, McNelly Sabine, von Weizsäcker Fritz, Merfort Irmgard, Maurer Ulrich, Strasser Andreas, Borner Christoph

机构信息

Institute of Molecular Medicine and Cell Research, (ZBMZ), Albert Ludwigs University Freiburg, Freiburg, Germany.

出版信息

Hepatology. 2008 Dec;48(6):1942-53. doi: 10.1002/hep.22541.

DOI:10.1002/hep.22541
PMID:19003879
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2993691/
Abstract

UNLABELLED

Fas/CD95-induced apoptosis of hepatocytes in vivo proceeds through the so-called type II pathway, requiring the proapoptotic BH3-only Bcl-2 family member Bid for mitochondrial death signaling. Consequently, Bid-deficient mice are protected from anti-Fas antibody injection induced fatal hepatitis. We report the unexpected finding that freshly isolated mouse hepatocytes, cultured on collagen or Matrigel, become independent of Bid for Fas-induced apoptosis, thereby switching death signaling from type II to type I. In such in vitro cultures, Fas ligand (FasL) activates caspase-3 without Bid cleavage, Bax/Bak activation or cytochrome c release, and neither Bid ablation nor Bcl-2 overexpression is protective. The type II to type I switch depends on extracellular matrix adhesion, as primary hepatocytes in suspension die in a Bid-dependent manner. Moreover, the switch is specific for FasL-induced apoptosis as collagen-plated Bid-deficient hepatocytes are protected from tumor necrosis factor alpha/actinomycin D (TNFalpha/ActD)-induced apoptosis.

CONCLUSION

Our data suggest a selective crosstalk between extracellular matrix and Fas-mediated signaling that favors mitochondria-independent type I apoptosis induction.

摘要

未标记

Fas/CD95诱导的体内肝细胞凋亡通过所谓的II型途径进行，需要仅含促凋亡BH3结构域的Bcl-2家族成员Bid参与线粒体死亡信号传导。因此，Bid缺陷型小鼠可免受抗Fas抗体注射诱导的致命性肝炎。我们报告了一个意外发现，即新鲜分离的小鼠肝细胞在胶原蛋白或基质胶上培养时，Fas诱导的凋亡不再依赖Bid，从而使死亡信号从II型转变为I型。在这种体外培养中，Fas配体（FasL）激活caspase-3时无需Bid裂解、Bax/Bak激活或细胞色素c释放，Bid缺失或Bcl-2过表达均无保护作用。从II型到I型的转变取决于细胞外基质黏附，因为悬浮培养的原代肝细胞以Bid依赖的方式死亡。此外，这种转变对FasL诱导的凋亡具有特异性，因为铺在胶原蛋白上的Bid缺陷型肝细胞可免受肿瘤坏死因子α/放线菌素D（TNFα/ActD）诱导的凋亡。

结论

我们的数据表明细胞外基质与Fas介导的信号传导之间存在选择性相互作用，有利于线粒体非依赖性I型凋亡诱导。

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