Abstract
Toll-like receptor 3 (TLR3), a member of the pathogen recognition receptors, is widely expressed in various cells and has been shown to activate immune signaling pathways by recognizing viral double-stranded RNA. Recently, it was reported that the activation of TLR3 induced apoptosis in some cells, but the detailed molecular mechanism is not fully understood. In this study, we found that in endothelial cells polyinosinic-polycytidylic acid (poly(I-C)) induced dose- and time-dependent cell apoptosis, which was elicited by TLR3 activation, as TLR3 neutralization and down-regulation repressed the apoptosis. Poly(I-C) induced the activation of both caspases 8 and 9, indicating that TLR3 triggered the signaling of both the extrinsic and intrinsic apoptotic pathways. Poly(I-C) up-regulated tumor necrosis factor-related apoptosis-inducing ligand and its receptors, death receptors 4/5, resulting in initiating the extrinsic pathway. Furthermore, poly(I-C) down-regulated anti-apoptotic protein, B cell lymphoma 2 (Bcl-2), and up-regulated Noxa, a key Bcl-2 homology 3-only antagonist of Bcl-2, leading to the priming of the intrinsic pathway. A p53-related protein, the transactivating p63 isoform α (TAp63α), was induced by TLR3 activation and contributed to the activation of both the intrinsic and extrinsic apoptotic pathways. Both the cells deficient in p63 gene expression by RNA interference and cells that overexpressed the N-terminally truncated p63 isoform α (ΔNp63α), a dominant-negative variant of TAp63α, by gene transfection, survived TLR3 activation. Taken together, TAp63α is a crucial regulator downstream of TLR3 to induce cell death via death receptors and mitochondria.
Highlights
Immune response and the priming of subsequent adaptive immune response by controlling multiple functions of dendritic cells [1, 2]
We found that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors 4/5 (DR4/5) and Noxa elicited the extrinsic and intrinsic apoptosis pathways, respectively, in tolllike receptor 3 (TLR3)-induced endothelial cell apoptosis, which was regulated by TAp63␣, a p53-related protein
We found that the treatment of resting primary human umbilical vein endothelial cells (HUVECs) with poly(I-C) for 24 h elicited a slight apoptotic effects
Summary
Immune response and the priming of subsequent adaptive immune response by controlling multiple functions of dendritic cells [1, 2]. We found that TRAIL death receptors 4/5 (DR4/5) and Noxa elicited the extrinsic and intrinsic apoptosis pathways, respectively, in TLR3-induced endothelial cell apoptosis, which was regulated by TAp63␣, a p53-related protein.
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