Hess S, Gottfried E, Smola H, Grunwald U, Schuchmann M, Engelmann H
Institute for Immunology, University of Munich, Germany.
Eur J Immunol. 1998 Nov;28(11):3594-604. doi: 10.1002/(SICI)1521-4141(199811)28:11<3594::AID-IMMU3594>3.0.CO;2-D.
CD40, a member of the TNF receptor family, has been characterized as an important T-B cell interaction molecule. In B cells it co-stimulates isotype switching, proliferation, adhesion and is involved in cell death regulation. In addition to B cells, CD40 expression was found on transformed cells and carcinomas. However, little is known about its functions in these cell types. Recent studies show that CD40 mediates the production of pro-inflammatory cytokines in non-hematopoietic cells, inhibits proliferation or induces cell death. In some cell types the apoptotic program triggered by CD40 is only executed when protein synthesis is blocked, suggesting the existence of constitutively expressed resistance proteins. Here we demonstrate that CD40, similar to the 55-kDa TNF receptor (p55TNFR), has a dual role in the regulation of apoptosis in such cells. In the fibroblast cell line SV80 both CD40 and the p55TNFR trigger apoptosis when protein synthesis is blocked with cycloheximide (CHX). Simultaneous activation of both receptors results in markedly enhanced cell death. However, CD40 activation more than 4 h prior to a challenge with TNF/CHX paradoxically conferred resistance to TNF-induced cell death. Protection correlated with NF-kappaB induction and up-regulation of the anti-apoptotic zinc finger protein A20. Overexpression of A20 in turn rendered SV80 cells resistant to TNF cytotoxicity. In conclusion, our data provide evidence that CD40 may regulate cell death in non-hematopoietic cells in a dual fashion: the decision upon apoptosis or survival of a CD40-activated cell seems to depend on its ability to up-regulate resistance factors.
CD40是肿瘤坏死因子受体家族的成员之一，已被确定为一种重要的T细胞与B细胞相互作用分子。在B细胞中，它能共刺激免疫球蛋白类型转换、增殖、黏附，并参与细胞死亡调控。除了B细胞外，在转化细胞和癌组织中也发现了CD40的表达。然而，对于其在这些细胞类型中的功能却知之甚少。最近的研究表明，CD40在非造血细胞中介导促炎细胞因子的产生，抑制增殖或诱导细胞死亡。在某些细胞类型中，由CD40触发的凋亡程序只有在蛋白质合成受阻时才会执行，这表明存在组成性表达的抗性蛋白。在此我们证明，与55 kDa肿瘤坏死因子受体（p55TNFR）类似，CD40在这类细胞的凋亡调控中具有双重作用。在用放线菌酮（CHX）阻断蛋白质合成时，成纤维细胞系SV80中的CD40和p55TNFR都会触发凋亡。两种受体同时激活会导致细胞死亡显著增强。然而，在用肿瘤坏死因子/放线菌酮刺激之前4小时以上激活CD40，反而会使细胞对肿瘤坏死因子诱导的细胞死亡产生抗性。这种保护作用与核因子κB的诱导以及抗凋亡锌指蛋白A20的上调相关。A20的过表达反过来又使SV80细胞对肿瘤坏死因子的细胞毒性产生抗性。总之，我们的数据证明，CD40可能以双重方式调节非造血细胞中的细胞死亡：CD40激活的细胞是凋亡还是存活，似乎取决于其上调抗性因子的能力。
