Both TNF receptors are required for direct TNF-mediated cytotoxicity in microvascular endothelial cells.

Abstract:

:The conditions under which tumor necrosis factor-alpha (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 (Tnfr1o mice) or TNFR2 (Tnfr2o mice) were incubated with TNF in the presence or absence of Act. D. Under sensitized conditions, Tnfr2o MVEC were lysed like controls, whereas Tnfr1o 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 Tnfr1o and Tnfr2o 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.

journal_name

Eur J Immunol

authors

Lucas R,Garcia I,Donati YR,Hribar M,Mandriota SJ,Giroud C,Buurman WA,Fransen L,Suter PM,Nunez G,Pepper MS,Grau GE

doi

10.1002/(SICI)1521-4141(199811)28:11<3577::AID-IMM

subject

Has Abstract

pub_date

1998-11-01 00:00:00

pages

3577-86

issue

11

eissn

0014-2980

issn

1521-4141

journal_volume

28

pub_type

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