Nowak M, Gaines G C, Rosenberg J, Minter R, Bahjat F R, Rectenwald J, MacKay S L, Edwards C K, Moldawer L L
Department of Surgery, University of Florida College of Medicine, Gainesville, Florida 32610, USA.
Am J Physiol Regul Integr Comp Physiol. 2000 May;278(5):R1202-9. doi: 10.1152/ajpregu.2000.278.5.R1202.
Lipopolysaccharide and D-galactosamine induced lethality and apoptotic liver injury is dependent on endogenously produced tumor necrosis factor (TNF)-alpha. The present study was undertaken to determine whether membrane-associated or secreted TNF-alpha signaling through the p55 or p75 receptor was responsible for survival and hepatic injury after lipopolysaccharide administration in D-galactosamine-sensitized mice. Transgenic mice expressing null forms of TNF-alpha, the p55 and p75 receptor, and mice expressing only a cell-associated form of TNF-alpha were challenged with 8 mg D-galactosamine and 100 ng lipopolysaccharide. Mortality and apoptotic liver injury were only seen in wild-type and p75 knockout mice. p75 Knockout mice had significantly higher concentrations of plasma TNF-alpha than any other experimental group (P </= 0.05) and tended to have the highest mortality and liver injury. In contrast, p55 and TNF-alpha knockout mice and animals expressing only a cell-associated form of TNF-alpha exhibited no mortality or liver injury. We conclude that survival and apoptotic liver injury in response to lipopolysaccharide and D-galactosamine are dependent exclusively on secreted TNF-alpha signaling through the p55 receptor.
脂多糖和D-半乳糖胺诱导的致死率及凋亡性肝损伤依赖于内源性产生的肿瘤坏死因子（TNF）-α。本研究旨在确定在D-半乳糖胺致敏的小鼠中，脂多糖给药后，通过p55或p75受体进行的膜相关或分泌型TNF-α信号传导是否对生存及肝损伤负责。用8毫克D-半乳糖胺和100纳克脂多糖对表达无效形式的TNF-α、p55和p75受体的转基因小鼠，以及仅表达细胞相关形式TNF-α的小鼠进行攻击。仅在野生型和p75基因敲除小鼠中观察到死亡率和凋亡性肝损伤。p75基因敲除小鼠的血浆TNF-α浓度显著高于其他任何实验组（P≤0.05），且死亡率和肝损伤往往最高。相比之下，p55和TNF-α基因敲除小鼠以及仅表达细胞相关形式TNF-α的动物未出现死亡或肝损伤。我们得出结论，对脂多糖和D-半乳糖胺的生存及凋亡性肝损伤仅依赖于通过p55受体进行的分泌型TNF-α信号传导。
