TY - JOUR
T1 - Both TNF receptors are required for direct TNF-mediated cytotoxicity in microvascular endothelial cells
AU - Lucas, Rudolf
AU - Garcia, Irene
AU - Donati, Yves R.A.
AU - Hribar, Marusa
AU - Mandriota, Stefano J.
AU - Giroud, Christine
AU - Buurman, Wim A.
AU - Fransen, Lucie
AU - Suter, Peter M.
AU - Muñez, Gabriel
AU - Pepper, Michael S.
AU - Grau, Georges E.
PY - 1998/11
Y1 - 1998/11
N2 - The conditions under which tumor necrosis factor-α (TNF) induces apoptosis in primary microvascular endothelial cells (MVEC) were investigated. In the absence of sensitizing agents, TNF induced apoptosis after 3 days of incubation in confluent MVEC. In contrast, upon addition of the transcriptional inhibitor actinomycin D (Act. D), confluence was no longer required and apoptosis occurred already after 16 h. To assess the role of either TNF receptor (TNFR) type in apoptosis, MVEC isolated from mice genetically deficient in TNFR1 (Tnfr1°mice) or TNFR2 (Tnfr2°mice) were incubated with TNF in the presence or absence of Act. D. Under sensitized conditions, Tnfr2°MVEC were lysed like controls, whereas Tnfr1°MVEC were completely resistant, indicating an exclusive role for TNFR1. In contrast, in the absence of Act. D, confluent monolayers of wild-type cells were lysed by TNF, but both Tnfr1°and Tnfr2°MVEC were resistant to TNF-mediated toxicity, indicating a requirement for both TNFR types. Overexpression of the anti-apoptotic protein bcl-xL in MVEC led to a protection against the direct, but not the sensitized cytotoxicity of TNF. In conclusion, in pathophysiologically relevant conditions, both TNFR appear to be required for TNF-induced apoptosis in MVEC.
AB - The conditions under which tumor necrosis factor-α (TNF) induces apoptosis in primary microvascular endothelial cells (MVEC) were investigated. In the absence of sensitizing agents, TNF induced apoptosis after 3 days of incubation in confluent MVEC. In contrast, upon addition of the transcriptional inhibitor actinomycin D (Act. D), confluence was no longer required and apoptosis occurred already after 16 h. To assess the role of either TNF receptor (TNFR) type in apoptosis, MVEC isolated from mice genetically deficient in TNFR1 (Tnfr1°mice) or TNFR2 (Tnfr2°mice) were incubated with TNF in the presence or absence of Act. D. Under sensitized conditions, Tnfr2°MVEC were lysed like controls, whereas Tnfr1°MVEC were completely resistant, indicating an exclusive role for TNFR1. In contrast, in the absence of Act. D, confluent monolayers of wild-type cells were lysed by TNF, but both Tnfr1°and Tnfr2°MVEC were resistant to TNF-mediated toxicity, indicating a requirement for both TNFR types. Overexpression of the anti-apoptotic protein bcl-xL in MVEC led to a protection against the direct, but not the sensitized cytotoxicity of TNF. In conclusion, in pathophysiologically relevant conditions, both TNFR appear to be required for TNF-induced apoptosis in MVEC.
KW - Apoptosis
KW - Endothelial cell
KW - TNF
KW - bcl-xL
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U2 - 10.1002/(sici)1521-4141(199811)28:11<3577::aid-immu3577>3.0.co;2-%23
DO - 10.1002/(sici)1521-4141(199811)28:11<3577::aid-immu3577>3.0.co;2-%23
M3 - Article
C2 - 9842900
AN - SCOPUS:0031795272
SN - 0014-2980
VL - 28
SP - 3577
EP - 3586
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 11
ER -