CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection.
CD40 activation induces apoptosis in cultured human hepatocytes via induction of cell surface fas ligand expression and amplifies fas-mediated hepatocyte death during allograft rejection.
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DOI：
10.1084/jem.189.2.441
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发表时间：
1999-01-18
期刊：
影响因子：
--
通讯作者：
Adams DH
中科院分区：
文献类型：
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作者：
Afford SC;Randhawa S;Eliopoulos AG;Hubscher SG;Young LS;Adams DH
我们提出一种新的肝细胞凋亡机制，涉及 CD40 和 Fas 之间的协同相互作用，参与慢性同种异体移植排斥反应的肝细胞损失。我们检测到肝细胞中 Fas、Fas 配体 (FasL) 和 CD40 的表达增加，这与慢性同种异体移植排斥中小叶中心（腺泡区 3）肝细胞的脱落相关。 CD40配体（CD40L）的表达也增加，但主要限于CD68+巨噬细胞。使用原代人肝细胞和 HepG2 细胞系在体外证明了 CD40 和 Fas 在肝细胞凋亡中的功能作用，在这两种细胞中，细胞凋亡不仅是通过直接交联 Fas 诱导的，而且还通过 CD40 激活诱导的。我们的数据表明，CD40 激活通过 Fas 诱导细胞凋亡，因为 (a) 连接 CD40 上调肝细胞 FasL 表达，以及 (b) FasL 中和单克隆抗体可阻止通过 CD40 激活诱导的细胞凋亡。因此，CD40 的参与会触发人肝细胞的凋亡，并可能在慢性排斥反应和涉及 Fas 介导的细胞凋亡的其他炎症性肝病中放大 Fas 依赖性肝细胞凋亡。
We propose that a novel mechanism of hepatocyte apoptosis, involving a cooperative interaction between CD40 and Fas, is involved in the hepatocyte loss of chronic liver allograft rejection. We detected increased hepatocyte expression of Fas, Fas ligand (FasL), and CD40 associated with dropout of centrilobular (acinar zone 3) hepatocytes in chronic allograft rejection. Expression of CD40 ligand (CD40L) was also increased but was largely restricted to CD68+ macrophages. A functional role for CD40 and Fas in hepatocyte apoptosis was demonstrated in vitro using primary human hepatocytes and the HepG2 cell line in both of which apoptosis was induced, not only by cross-linking Fas directly but also via CD40 activation. Our data suggest that CD40 activation induces apoptosis via Fas because (a) ligation of CD40 upregulated hepatocyte FasL expression, and (b) apoptosis induced via activation of CD40 was prevented by a neutralizing monoclonal antibody to FasL. Thus, CD40 engagement triggers apoptosis of human hepatocytes and might amplify Fas-dependent hepatocyte apoptosis in chronic rejection and other inflammatory liver diseases in which Fas-mediated apoptosis is involved.