Brown D M, Phipps R P
Cancer Center, University of Rochester, School of Medicine and Dentistry, NY 14642, USA.
J Immunol. 1996 Aug 15;157(4):1359-70.
Apoptosis is a critical mechanism in the maturation and maintenance of the immune system. However, the process by which cells die remains poorly understood. The proto-oncogene bcl-2 is considered important in determining whether cells enter an apoptotic pathway or survive. In this report, we first examined the differential sensitivity of immature (CH31) and mature (CH12) B cell lymphomas to growth inhibition by PGE2. The CH31 cell line was growth inhibited and underwent apoptosis in response to PGE2, unlike its mature counterpart, CH12. Furthermore, endogenous levels of the anti-apoptotic protein Bcl-2 in CH31 cells were low compared with CH12. To further investigate the role of Bcl-2 in PGE2- and cAMP-mediated cell death, a retroviral vector bearing the human bcl-2 gene was introduced into CH31. High expression of Bcl-2 in CH31 had no effect on growth inhibition induced by PGE2 or dibutyryl cAMP. In contrast, increased expression of Bcl-2 completely inhibited PGE2- and cAMP-mediated DNA fragmentation and nuclear condensation. Finally, cell cycle analysis of Bcl-2-expressing CH31 cells demonstrated that PGE2 increased the percentage of cells in G1, and analysis of synchronized populations revealed that PGE2 acts at all phases of the cell cycle to delay normal progression. These results support the hypothesis that apoptosis induced through PGE2 and cAMP signaling is sensitive to regulation by Bcl-2 in CH31 B cell lymphomas. Furthermore, unlike apoptosis, regulation of PGE2- and cAMP-mediated growth inhibition in B lineage cells is a distinct and Bcl-2-independent mechanism.
细胞凋亡是免疫系统成熟和维持过程中的关键机制。然而，细胞死亡的过程仍知之甚少。原癌基因bcl-2被认为在决定细胞是进入凋亡途径还是存活方面很重要。在本报告中，我们首先研究了未成熟（CH31）和成熟（CH12）B细胞淋巴瘤对PGE2诱导的生长抑制的不同敏感性。与成熟的CH12细胞系不同，CH31细胞系受到PGE2的生长抑制并发生凋亡。此外，与CH12相比，CH31细胞中抗凋亡蛋白Bcl-2的内源性水平较低。为了进一步研究Bcl-2在PGE2和cAMP介导的细胞死亡中的作用，将携带人bcl-2基因的逆转录病毒载体导入CH31细胞。CH31细胞中Bcl-2的高表达对PGE2或二丁酰cAMP诱导的生长抑制没有影响。相反，Bcl-2表达的增加完全抑制了PGE2和cAMP介导的DNA片段化和核浓缩。最后，对表达Bcl-2的CH31细胞进行细胞周期分析表明，PGE2增加了G1期细胞的百分比，对同步化群体的分析表明，PGE2在细胞周期的所有阶段都起作用，以延迟正常进程。这些结果支持这样的假设，即通过PGE2和cAMP信号诱导的细胞凋亡在CH31 B细胞淋巴瘤中对Bcl-2的调节敏感。此外，与细胞凋亡不同，B系细胞中PGE2和cAMP介导的生长抑制的调节是一种独特的、不依赖Bcl-2的机制。
