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Lipopolysaccharide signals an endothelial apoptosis pathway through TNF receptor-associated factor 6-mediated activation of c-Jun NH2-terminal kinase

Lipopolysaccharide signals an endothelial apoptosis pathway through TNF receptor-associated factor 6-mediated activation of c-Jun NH2-terminal kinase
Lipopolysaccharide signals an endothelial apoptosis pathway through TNF receptor-associated factor 6-mediated activation of c-Jun NH2-terminal kinase
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-kappaB conveys an important survival signal. In contrast, even though LPS can also activate NF-kappaB, 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-kappaB nuclear translocation and c-Jun NH(2)-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.
0022-1767
2611-2618
Hull, Christopher
69e36d4b-1708-4b02-a16a-e0d5d0858d30
McLean, Graeme
8f22b391-443d-4dc1-9a4d-b7ec12009321
Wong, Fred
f163e691-cc42-4de6-bd76-0abde9539ce8
Duriez, Patrick J.
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Karsan, Aly
4e7a164d-e912-42e1-9647-201067b473cc
Hull, Christopher
69e36d4b-1708-4b02-a16a-e0d5d0858d30
McLean, Graeme
8f22b391-443d-4dc1-9a4d-b7ec12009321
Wong, Fred
f163e691-cc42-4de6-bd76-0abde9539ce8
Duriez, Patrick J.
4cf499bc-007a-43b3-b180-d6e5dc3d151b
Karsan, Aly
4e7a164d-e912-42e1-9647-201067b473cc

Hull, Christopher, McLean, Graeme, Wong, Fred, Duriez, Patrick J. and Karsan, Aly (2002) Lipopolysaccharide signals an endothelial apoptosis pathway through TNF receptor-associated factor 6-mediated activation of c-Jun NH2-terminal kinase. Journal of Immunology, 169 (5), 2611-2618. (PMID:12193732)

Record type: Article

Abstract

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-kappaB conveys an important survival signal. In contrast, even though LPS can also activate NF-kappaB, 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-kappaB nuclear translocation and c-Jun NH(2)-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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Published date: 1 September 2002

Identifiers

Local EPrints ID: 164821
URI: http://eprints.soton.ac.uk/id/eprint/164821
ISSN: 0022-1767
PURE UUID: 4df06a2a-8175-422e-84a6-acbc1191ca6b
ORCID for Patrick J. Duriez: ORCID iD orcid.org/0000-0003-1814-2552

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Date deposited: 04 Oct 2010 13:34
Last modified: 12 Jul 2022 01:41

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Contributors

Author: Christopher Hull
Author: Graeme McLean
Author: Fred Wong
Author: Patrick J. Duriez ORCID iD
Author: Aly Karsan

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