Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis
Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis
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DOI：
10.1002/hep.21257
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发表时间：
2006-08-01
期刊：
影响因子：
13.5
通讯作者：
Benihoud, Karim
中科院分区：
文献类型：
--
作者：
Descamps, Delphyne;Vigant, Frederic;Benihoud, Karim
Fas和肿瘤坏死因子受体1（TNFR 1）是参与各种疾病，如肝炎，败血症，或移植排斥反应的死亡受体。死亡配体或可溶性死亡受体的中和抗体可以抑制细胞死亡;然而，由于它们的全身作用，它们诱导副作用。为了特异性地阻断死亡信号传导至靶细胞，我们创建了死亡结构域缺陷（Delta DD）膜锚定受体，通过重组腺病毒或非病毒重组质粒的流体动力学压力递送至肝脏。在抗Fas抗体诱导的暴发性肝炎中，在其肝脏中表达重组Fas诱饵受体（Fas Delta DD）的小鼠完全免受细胞凋亡的影响，并在暴发性肝炎中存活。在T细胞依赖性伴刀豆球蛋白A诱导的自身免疫性肝炎中，Fas Delta DD拮抗剂表达可防止肝细胞损伤和小鼠死亡。最后，TNF 1 Delta DD有效地保护小鼠免受LPS诱导的脓毒性休克。总之，这种Delta DD-诱饵受体作为显性负性受体发挥局部抑制作用，同时避免凋亡配体的全身中和，并可能在肝炎中具有治疗潜力。
Fas and tumor necrosis factor receptor 1 (TNFR1) are death receptors involved in various diseases such as hepatitis, sepsis, or graft rejection. Neutralizing antibodies to death ligands or soluble death receptors can inhibit cell death; however, they induce side effects because of their systemic actions. To specifically block death signaling to target cells, we created death domain-deficient (Delta DD) membrane-anchored receptors, delivered to the liver by either recombinant adenovirus or hydrodynamic pressure of nonviral recombinant plasmids. In anti-Fas antibody-induced fulminant hepatitis, mice expressing recombinant Fas-decoy receptors (Fas Delta DD) in their livers were completely protected against apoptosis and survived fulminant hepatitis. In T-cell-dependent concanavalin A-induced autoimmune hepatitis, Fas Delta DD antagonist expression prevented hepatocyte damage and mouse death. Finally, TNF1 Delta DD effectively protected mice against LPS-induced septic shock. In conclusion, such Delta DD-decoy receptors act as dominant-negative receptors exerting local inhibition, while avoiding systemic neutralization of apoptosis ligands, and might have therapeutic potential in hepatitis.