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- Title
Inhibition of phosphatidylinositol-3 kinase/Akt or mitogen-activated protein kinase signaling sensitizes endothelial cells to TNF-α cytotoxicity.
- Authors
Zhang, L; Himi, T; Morita, I; Murota, S
- Abstract
Bovine carotid artery endothelial (BAE) cells are resistant to tumor necrosis factor-α (TNF), like most other cells. We examined if mitogen-activated protein (MAP) kinase and phosphatidylinositol-3 (PI3) kinase/Akt pathways are involved in this effect. In BAE cells, TNF activates MAP kinase in a MAP kinase kinase 1 (MEK1) manner and Akt in PI3-kinasedependent manner. Pretreatment with either the MEK1 inhibitor U0126 or PI3-kinase inhibitor LY294002 sensitized BAE cells to TNF-induced apoptosis. Neither U0126 nor LY294002 pretreatment affected TNF-induced activation of NF-κB, suggesting that the MAP kinase or PI3-kinase/Aktmediated anti-apoptotic effect induced by TNF was not relevant to NF-κB activation. Both MAP kinase and PI3kinase/Akt -mediated signaling could prevent cytochrome c release and mitochondrial transmembrane potential (Δψ) decrease. PI3-kinase/Akt signaling attenuated caspase-8 activity, whereas MAP kinase signaling impaired caspase-9 activity. These results suggest that TNF-induced MAP kinase and PI3-kinase/Akt signaling play important roles in protecting BAE cells from TNF cytotoxicity.
- Subjects
PROTEIN kinases; TUMOR necrosis factors; CELL death
- Publication
Cell Death & Differentiation, 2001, Vol 8, Issue 5, p528
- ISSN
1350-9047
- Publication type
Article
- DOI
10.1038/sj.cdd.4400838