Katschinski D M, Robins H I, Schad M, Frede S, Fandrey J
Institute of Physiology, Medical University of Lübeck, Germany.
Cancer Res. 1999 Jul 15;59(14):3404-10.
We used the human myelomonoblastic leukemia cell line PLB-985 to study the effects of temperatures ranging from 37 degrees C to 43 degrees C for 1 h on the induction of apoptosis and cell cycle distribution in leukemia cells. The threshold temperature for the onset of apoptosis was 42 degrees C. Whereas hyperthermia exerted no effect on the expression of Bcl-2 and Bax, heat induced a >30-fold increase of tumor necrosis factor (TNF) alpha mRNA expression and a significant increase in TNF-alpha protein secretion. This endogenous production of TNF-alpha correlated directly with the temperature-induced apoptode effect. Blocking TNF-alpha expression via treatment with pyrrolidinedithiocarbamate or blocking TNF-alpha activity with neutralizing antibodies abrogated heat-provoked apoptosis. In addition, exposure of cell culture supernatant of heat-treated PLB-985 cells to untreated cells induced an apoptotic effect. These data indicate a TNF-a-mediated self eradication of the leukemia cells after heat exposure. Inducing apoptosis with wild-type TNF-alpha or p55 and p75 protein muteins demonstrated that this effect was mediated by the p55 receptor. Interestingly, the autocrine suicidal loop found in immature leukemia cells was lost after granulocytic differentiation with 0.5% N,N-dimethylformamide. These data should be of critical importance for the understanding of the biological impact of fever as well as for developing therapeutic approaches to malignant diseases
我们使用人骨髓单核细胞白血病细胞系PLB-985来研究37摄氏度至43摄氏度温度范围持续1小时对白血病细胞凋亡诱导及细胞周期分布的影响。凋亡起始的阈值温度为42摄氏度。高温对Bcl-2和Bax的表达无影响，但热诱导肿瘤坏死因子（TNF）α mRNA表达增加30倍以上，且TNF-α蛋白分泌显著增加。这种内源性TNF-α的产生与温度诱导的凋亡效应直接相关。通过用吡咯烷二硫代氨基甲酸盐处理阻断TNF-α表达或用中和抗体阻断TNF-α活性可消除热引发的凋亡。此外，将热处理的PLB-985细胞的细胞培养上清液暴露于未处理细胞可诱导凋亡效应。这些数据表明热暴露后白血病细胞通过TNF-α介导的自我清除。用野生型TNF-α或p55和p75蛋白突变体诱导凋亡表明这种效应是由p55受体介导的。有趣的是，用0.5% N，N-二甲基甲酰胺进行粒细胞分化后，在未成熟白血病细胞中发现的自分泌自杀环消失了。这些数据对于理解发热的生物学影响以及开发恶性疾病的治疗方法至关重要。
