Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-kappaB and c-Jun N-terminal kinase.
The intracellular pathways by which inflammatory mediators transmit their angiogenic signals is not well studied. The effects of a potent inflammatory mediator, bacterial lipopolysaccharide (LPS), are transmitted through Toll-like receptors (TLRs). A major, although not exclusive, LPS/TLR intracellular signaling pathway is routed through TNF (tumor necrosis factor) receptor associated factor 6 (TRAF6). In this report we demonstrate that LPS directly stimulates endothelial sprouting in vitro. By blocking TRAF6 activity using retroviral expression of a dominant-negative TRAF6 in endothelial cells, we show that TRAF6 is absolutely required for the LPS-initiated angiogenic response in vitro and in vivo. Inhibition of either c-Jun N-terminal kinase (JNK) activity or nuclear factor kappaB (NF-kappaB) activity, downstream of TRAF6, is sufficient to inhibit LPS-induced endothelial sprouting. In contrast, only inhibition of NF-kappaB, but not JNK, activity blocks basic fibroblast growth factor (bFGF)-induced angiogenesis. Our findings thus demonstrate a direct endothelial-stimulatory role of LPS in initiating angiogenesis through activation of TRAF6-dependent signaling pathways.
Pollet
Ingrid
I
Department of Medical Biophyics, British Columbia Cancer Research Centre, 601 West 10th Ave, Vancouver, BC, Canada, V5Z 1L3.
Opina
Christy J
CJ
Zimmerman
Carla
C
Leong
Kevin G
KG
Wong
Fred
F
Karsan
Aly
A
D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D002823:Chorion / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6
D008070:Lipopolysaccharides; D016328:NF-kappa B; D011506:Proteins; D048029:TNF Receptor-Associated Factor 6; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases