Abstract: Tumor necrosis factor α (TNF-α) influences endothelial cell viability by altering the regulatory molecules involved in induction or suppression of apoptosis. However, the underlying mechanisms are still not completely understood. In this study, we demonstrated that A20 (also known as TNFAIP3, tumor necrosis factor α-induced protein 3, and an anti-apoptotic protein) regulates the inhibitor of apoptosis protein-2 (cIAP-2) expression upon TNF-α induction in endothelial cells. Inhibition of A20 expression by its siRNA resulted in attenuating expression of TNF-α-induced cIAP-2, yet not cIAP-1 or XIAP. A20-induced cIAP-2 expression can be blocked by the inhibition of phosphatidyl inositol-3 kinase (PI3-K), but not nuclear factor (NF)-κB, while concomitantly increasing the number of endothelial apoptotic cells and caspase 3 activation. Moreover, TNF-α-mediated induction of apoptosis was enhanced by A20 inhibition, which could be rescued by cIAP-2. Taken together, these results identify A20 as a cytoprotective factor involved in cIAP-2 inhibitory pathway of TNF-α-induced apoptosis. This is consistent with the idea that endothelial cell viability is dependent on interactions between inducers and suppressors of apoptosis, susceptible to modulation by TNF-α.
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Guo, S.; Messmer-Blust, A.F.; Wu, J.; Song, X.; Philbrick, M.J.; Shie, J.-L.; Rana, J.S.; Li, J. Role of A20 in cIAP-2 Protection against Tumor Necrosis Factor α (TNF-α)-Mediated Apoptosis in Endothelial Cells. Int. J. Mol. Sci. 2014, 15, 3816-3833.
Guo S, Messmer-Blust AF, Wu J, Song X, Philbrick MJ, Shie J-L, Rana JS, Li J. Role of A20 in cIAP-2 Protection against Tumor Necrosis Factor α (TNF-α)-Mediated Apoptosis in Endothelial Cells. International Journal of Molecular Sciences. 2014; 15(3):3816-3833.
Guo, Shuzhen; Messmer-Blust, Angela F.; Wu, Jiaping; Song, Xiaoxiao; Philbrick, Melissa J.; Shie, Jue-Lon; Rana, Jamal S.; Li, Jian. 2014. "Role of A20 in cIAP-2 Protection against Tumor Necrosis Factor α (TNF-α)-Mediated Apoptosis in Endothelial Cells." Int. J. Mol. Sci. 15, no. 3: 3816-3833.