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Previous Article | Table of Contents | Next Article 
Critical involvement of transmembrane tumor necrosis factor-alpha in
endothelial programmed cell death mediated by ionizing radiation and
bacterial endotoxin
G Eissner, F Kohlhuber, M Grell, M Ueffing, P Scheurich, A Hieke, G Multhoff, GW Bornkamm and E Holler
GSF-Institut fur Klinische Molekularbiologie und Klinische Hamatologie,
Munchen, Germany.
In this report, we show that ionizing radiation (IR) at a clinically
relevant dose (4 Gy) causes apoptosis in macrovascular and microvascular
human endothelial cells. Treatment of irradiated cells with a low dose of
bacterial endotoxin (LPS), similar to the levels observed in serum during
endotoxemia, enhanced the rate of apoptosis, although LPS alone was unable
to induce programmed cell death. The cytokine and endotoxin antagonist
interleukin-10 (IL-10) reduced the rate of LPS + IR-induced apoptosis to
levels obtained with irradiation alone. Using neutralizing 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. However, further
analysis strongly suggested the transmembrane form of TNF (mTNF), but not
soluble TNF, to be accountable for the LPS-mediated cytotoxic effects.
Studies with anatagonistic receptor specific antibodies clearly showed that
TNF receptor type I (TR60) is essential and sufficient 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 used for conditioning in bone marrow
transplantation and that may thus contribute to transplant related
complications, especially in association with endotoxemia or related
inflammatory states.
Volume 86,
Issue 11,
pp. 4184-4193,
12/01/1995
Copyright © 1995 by The American Society of Hematology

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