Memon S A, Moreno M B, Petrak D, Zacharchuk C M
Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
J Immunol. 1995 Nov 15;155(10):4644-52.
Overexpression of Bcl-2 can prevent or markedly delay cell death induced by a variety of apoptotic stimuli. Although Fas and Fas ligand (FasL) interactions play a major role in the elimination of self-reactive T cells in the periphery, inhibition of Fas-mediated killing by Bcl-2 has not been consistently observed. The mouse T hybridoma 2B4.11 (2B4) has been a useful model to study glucocorticoid- and activation-induced apoptosis, which is mediated through Fas and FasL. Using both stable transfectants and transient transfections, overexpression of Bcl-2 or Bcl-xL readily blocked glucocorticoid-induced but not activation-induced apoptosis of 2B4 cells. Bcl-2 expression did not inhibit Fas-mediated cytotoxicity triggered by cells expressing FasL or by the transient transfection of human Fas. Similarly, overexpression of Bcl-2 in the mouse T hybridoma A1.1 did not block activation-induced/Fas-mediated apoptosis. In Jurkat cells, however, expression of Bcl-2 partially inhibited anti-Fas-induced cell death. A Bcl-2-related protein that can interfere with anti-Fas killing, the adenoviral E1B 19K, also did not block activation-induced/Fas-mediated apoptosis in 2B4 cells. In contrast, expression of CrmA, a cowpox virus protein that inhibits ICE-like protease activity, blocked activation-induced apoptosis in 2B4 cells but had little effect on Dex-mediated cytotoxicity. These results show that: 1) Bcl-2 can have strikingly different anti-cell death activity in the same cell depending upon the apoptotic stimulus, 2) distinct apoptosis signaling pathways may exist with differential sensitivity to Bcl-2 and ICE-like protease inhibitors.
Bcl-2的过表达能够预防或显著延迟由多种凋亡刺激所诱导的细胞死亡。尽管Fas与Fas配体（FasL）的相互作用在清除外周血中自身反应性T细胞方面发挥着主要作用，但Bcl-2对Fas介导的杀伤作用的抑制作用却并未得到一致的观察结果。小鼠T杂交瘤2B4.11（2B4）一直是研究糖皮质激素和激活诱导的凋亡的有用模型，这种凋亡是通过Fas和FasL介导的。利用稳定转染子和瞬时转染技术，Bcl-2或Bcl-xL的过表达能够轻易阻断糖皮质激素诱导的2B4细胞凋亡，但不能阻断激活诱导的凋亡。Bcl-2的表达并未抑制由表达FasL的细胞或人Fas的瞬时转染所触发的Fas介导的细胞毒性。同样，在小鼠T杂交瘤A1.1中Bcl-2的过表达也不能阻断激活诱导的/Fas介导的凋亡。然而，在Jurkat细胞中，Bcl-2的表达部分抑制了抗Fas诱导的细胞死亡。一种能够干扰抗Fas杀伤作用的Bcl-2相关蛋白，腺病毒E1B 19K，也不能阻断2B4细胞中激活诱导的/Fas介导的凋亡。相比之下，一种抑制ICE样蛋白酶活性的牛痘病毒蛋白CrmA的表达，阻断了2B4细胞中激活诱导的凋亡，但对地塞米松介导的细胞毒性影响很小。这些结果表明：1）在同一细胞中，Bcl-2根据凋亡刺激的不同可能具有显著不同的抗细胞死亡活性；2）可能存在对Bcl-2和ICE样蛋白酶抑制剂敏感性不同的不同凋亡信号通路。
