Laytragoon-Lewin N, Duhony E, Bai X F, Mellstedt H
Department of Experimental Oncology, Uppsala University, Stockholm, Sweden.
Eur J Haematol. 1998 Oct;61(4):266-71. doi: 10.1111/j.1600-0609.1998.tb01713.x.
Cross-linking of the CD40 receptors has been shown to induce protein tyrosine kinases (PTK) phosphorylation and prevent apoptosis in Bcl-2 negative germinal center B cells. The expression of CD40 on B chronic lymphocytic leukemia (B-CLL) cells was found to be similar to that of normal B cells. Activation of normal B cells with soluble anti-CD40 monoclonal antibody (mAb) induced tyrosine phosphorylation, prolonged survival and prevented apoptosis. However, activation of CD40 on B-CLL cells using soluble anti-CD40 mAb does not influence survival or apoptosis. Normal B cells entered apoptosis when cultured in the presence of soluble anti-CD95 mAb. This process was independent of PTK activity. On B-CLL cells, the CD95 molecules were downregulated and a transient PTK signal was observed when cross-linking of the receptor by soluble anti-CD95 mAb occurred. Interestingly, B-CLL cells did not enter apoptosis in the presence of anti-CD95 mAb. Our study indicates that survival signals mediated through the CD40 molecule and death signals mediated through the CD95 molecule used different intracellular pathways in control donor B cells. In contrast, B-CLL cells do not respond to these signals. The leukemic B cells showed a defective CD40-mediated signal transduction and downregulated CD95 receptor expression. As a consequence, no apoptosis could be induced in B-CLL cells by a soluble anti-CD95 mAb. The abnormalities of these receptors may contribute to the long-lived status of B-CLL cells.
已表明CD40受体的交联可诱导蛋白酪氨酸激酶（PTK）磷酸化，并防止Bcl-2阴性生发中心B细胞凋亡。发现B慢性淋巴细胞白血病（B-CLL）细胞上CD40的表达与正常B细胞相似。用可溶性抗CD40单克隆抗体（mAb）激活正常B细胞可诱导酪氨酸磷酸化、延长存活时间并防止凋亡。然而，使用可溶性抗CD40 mAb激活B-CLL细胞上的CD40并不影响其存活或凋亡。正常B细胞在可溶性抗CD95 mAb存在的情况下培养时会进入凋亡。这个过程与PTK活性无关。在B-CLL细胞上，CD95分子下调，当可溶性抗CD95 mAb使受体交联时，可观察到短暂的PTK信号。有趣的是，在抗CD95 mAb存在的情况下，B-CLL细胞不会进入凋亡。我们的研究表明，通过CD40分子介导的存活信号和通过CD95分子介导的死亡信号在对照供体B细胞中使用不同的细胞内途径。相比之下，B-CLL细胞对这些信号无反应。白血病B细胞显示出有缺陷的CD40介导的信号转导以及下调的CD95受体表达。因此，可溶性抗CD95 mAb无法诱导B-CLL细胞凋亡。这些受体的异常可能导致B-CLL细胞的长寿状态。
