LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted TNF-α and the TNF-p55 receptor
LPS-induced liver injury in D-galactosamine-sensitized mice requires secreted TNF-α and the TNF-p55 receptor
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DOI：
10.1152/ajpregu.2000.278.5.r1202
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发表时间：
2000-05-01
影响因子：
2.8
通讯作者：
Moldawer, LL
中科院分区：
文献类型：
--
作者：
Nowak, M;Gaines, GC;Moldawer, LL
内毒素和D-氨基半乳糖诱导的致死性和凋亡性肝损伤依赖于内源性产生的肿瘤坏死因子-α。本研究旨在确定膜相关或通过p55或p75受体分泌的肿瘤坏死因子-α信号是否与脂多糖对D-氨基半乳糖致敏小鼠的存活和肝损伤有关。用8毫克D-氨基半乳糖和100纳克脂多糖对表达空形式的肿瘤坏死因子-α(p55和p75受体)的转基因小鼠和只表达细胞相关形式的肿瘤坏死因子-α的小鼠进行攻击。死亡率和肝损伤仅见于野生型和p75基因敲除小鼠，p75基因敲除小鼠的血浆肿瘤坏死因子-α浓度显著高于其他任何实验组(P<0.05或等于0.05)，且死亡率和肝损伤倾向于最高。相反，p55和肿瘤坏死因子-α基因敲除的小鼠和只表达细胞相关形式的肿瘤坏死因子-α的小鼠和动物没有表现出死亡率或肝脏损伤。我们得出结论，内毒素和D-氨基半乳糖所致的存活和肝损伤的凋亡性损伤完全依赖于通过p55受体分泌的肿瘤坏死因子-α信号。
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 less than or equal to 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.