Lipopolysaccharide initiates a TRAF6-mediated endothelial survival signal.
Similar to tumor necrosis factor (TNF), bacterial lipopolysaccharide (LPS) elicits parallel apoptotic and antiapoptotic pathways in endothelial cells. The overall result is that there is minimal endothelial cell death in response to LPS without inhibition of the cytoprotective pathway. While the TNF-induced death and survival pathways have been relatively well elucidated, much remains to be learned about LPS signaling events in this regard. It is known that the transcription factor nuclear factor-kappaB (NF-kappaB) provides a critical cell survival signal in response to TNF, but is not an essential component of the LPS-induced survival pathway. The TNF receptor-associated factor 6 (TRAF6) is a major effector of multiple LPS-induced signals, including a c-Jun N-terminal kinase (JNK)-mediated apoptotic response. In this report we demonstrate that following LPS stimulation, TRAF6 also transmits an important endothelial cell survival signal in a situation of complete NF-kappaB blockade. In response to LPS, TRAF6 activates the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway, but not ERK1/2 mitogen-activated protein kinases (MAPKs) in endothelial cells. Activation of PI3K signals a critical antiapoptotic pathway in response to LPS in endothelial cells, whereas ERK1/2 does not. Thus TRAF6 acts as a bifurcation point of the LPS-initiated death and survival signals in endothelial cells.
Department of Pathology and Laboratory Medicine, British Columbia Cancer Agency, Vancouver, BC, Canada V5Z 1L3.
Fred
F
Wong
Christopher
C
Hull
Rachel
R
Zhande
Jennifer
J
Law
Aly
A
Karsan
D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020672:I-kappa B Proteins / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008833:Microcirculation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D048029:TNF Receptor-Associated Factor 6
D017304:Annexin A5; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D011506:Proteins; D048029:TNF Receptor-Associated Factor 6; D000072000:NF-KappaB Inhibitor alpha; D020169:Caspases