CRITICAL INVOLVEMENT OF TRANSMEMBRANE TUMOR-NECROSIS-FACTOR-ALPHA IN ENDOTHELIAL PROGRAMMED CELL-DEATH MEDIATED BY IONIZING-RADIATION AND BACTERIAL-ENDOTOXIN

In this report, we show that ionizing radiation (IR) at a clinically r elevant dose (4 Gy) causes apoptosis in macrovascular and microvascula r human endothelial cells. Treatment of irradiated cells with a low do se of bacterial endotoxin (LPS), similar to the levels observed in ser um during endotoxemia, enhanced the rate of apoptosis, although LPS al one was unable to induce programmed cell death. The cytokine and endot oxin antagonist interleukin-10 (IL-10) reduced the rate of LPS + IR-in duced apoptosis to levels obtained with irradiation alone. Using neutr alizing antibodies against tumor necrosis factor-alpha (TNF), we could show crucial involvement of TNF in the LPS-mediated enhancement of IR -induced apoptosis. but not in the IR-induced apoptosis per se. Howeve r, further analysis strongly suggested the transmembrane form of TNF ( mTNF), but not soluble TNF, to be accountable for the LPS-mediated cyt otoxic effects. Studies with anatagonistic receptor specific antibodie s clearly showed that TNF receptor type I (TR60) is essential and suff icient to elicit this effect. These findings are of potential clinical importance because they may disclose a relevant mechanism that leads to endothelial damage after radiotherapy or total body irradiation use d for conditioning in bone marrow transplantation and that may thus co ntribute to transplant related complications, especially in associatio n with endotoxemia or related inflammatory states. (C) 1995 by The Ame rican Society of Hematology.