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* Departments of Pathology and Laboratory Medicine, and Medical Biophysics, British Columbia Cancer Agency, British Columbia, Canada; and Departments of
Pathology and Laboratory Medicine and
Experimental Medicine, University of British Columbia, British Columbia, Canada
Inflammatory mediators such as TNF and bacterial LPS do not cause
significant apoptosis of endothelial cells unless the expression of
cytoprotective genes is blocked. In the case of TNF, the transcription
factor NF-
B conveys an important survival signal. In contrast, even
though LPS can also activate NF-B, this signal is dispensable for
LPS-inducible cytoprotective activity. LPS intracellular signals are
transmitted through a member of the Toll-like receptor family, TLR4.
This family of receptors transduces signals through a downstream
molecule, TNFR-associated factor 6 (TRAF6). In this study, we
demonstrate that the C-terminal fragment of TRAF6 (TRAF6-C) inhibits
LPS-induced NF-B nuclear translocation and c-Jun
NH2-terminal kinase (JNK) activation in endothelial cells.
In contrast, LPS activation of p38 kinase is not inhibited by TRAF6-C.
TRAF6-C also inhibits LPS-initiated endothelial apoptosis, but
potentiates TNF-induced apoptosis. LPS-induced loss of mitochondrial
transmembrane potential, cytochrome c release, and
caspase activation are all blocked by TRAF6-C. We demonstrate that
TRAF6 signals apoptosis via JNK activation, since inhibition of JNK
activation using a dominant-negative mutant also inhibits apoptosis.
JNK inhibition blocks caspase activation, but the reverse is not true.
Hence, JNK activation lies upstream of caspase activation in response
to LPS stimulation.
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