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Role of Tumor Necrosis Factor in Hyperthermia-induced Apoptosis of Human Leukemia Cells

Institute of Physiology, Medical University of Lübeck, D-23538 Lübeck, Germany [D. M. K., M. S., J. F.]; Comprehensive Cancer Center, University of Wisconsin, Madison, Wisconsin 53792 [H. I. R.]; and Institute of Physiology, University of Bonn, 53115 Bonn, Germany [S. F.]

We used the human myelomonoblastic leukemia cell line PLB-985 to study the effects of temperatures ranging from 37°C to 43°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°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) mRNA expression and a significant increase in TNF- protein secretion. This endogenous production of TNF- correlated directly with the temperature-induced apoptotic effect. Blocking TNF- expression via treatment with pyrrolidinedithiocarbamate or blocking TNF- 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--mediated self eradication of the leukemia cells after heat exposure. Inducing apoptosis with wild-type TNF- 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.

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