Zhou Bing-Rong, Gumenscheimer Marina, Freudenberg Marina-A, Galanos Chris
Department of Microbiology, Second Military Medical University, Shanghai, China.
World J Gastroenterol. 2005 Jun 14;11(22):3398-404. doi: 10.3748/wjg.v11.i22.3398.
To investigate whether induction of tolerance of mice to lipopolysaccharide (LPS) was able to inhibit apoptotic reaction in terms of characteristic DNA fragmentation and protect mice from lethal effect.
Experimental groups of mice were pretreated with non-lethal amount of LPS (0.05 microg). Both control and experimental groups simultaneously were challenged with LPS plus D-GalN for 6-7 h. The evaluations of both DNA fragmentations from the livers and the protection efficacy against lethality to mice through induction of tolerance to LPS were conducted.
In the naive mice challenge with LPS plus D-GalN resulted in complete death in 24 h, whereas a characteristic apoptotic DNA fragmentation was exclusively seen in the livers of mice receiving LPS in combination with D-GalN. The mortality in the affected mice was closely correlated to the onset of DNA fragmentation. By contrast, in the mice pre-exposed to LPS, both lethal effect and apoptotic DNA fragmentation were suppressed when challenged with LPS/D-GalN. In addition to LPS, the induction of mouse tolerance to TNF also enabled mice to cross-react against death and apoptotic DNA fragmentation when challenged with TNF and/or LPS in the presence of D-GalN. Moreover, this protection effect by LPS could last up to 24 h. TNFR1 rather than TNFR2 played a dual role in signaling pathway of either induction of tolerance to LPS for the protection of mice from mortality or inducing morbidity leading to the death of mice.
The mortality of D-GalN-treated mice in response to LPS was exceedingly correlated to the onset of apoptosis in the liver, which can be effectively suppressed by brief exposure of mice to a minute amount of LPS. The induced tolerance status was mediated not only by LPS but also by TNF. The developed tolerance to either LPS or TNF can be reciprocally cross-reacted between LPS and TNF challenges, whereas the signaling of induction of tolerance and promotion of apoptosis was through TNFR1, rather than TNFR2.
研究诱导小鼠对脂多糖（LPS）产生耐受性是否能够根据特征性DNA片段化抑制凋亡反应，并保护小鼠免受致死效应。
用非致死量的LPS（0.05微克）预处理实验组小鼠。对照组和实验组同时用LPS加D-半乳糖胺攻击6-7小时。对肝脏的DNA片段化以及通过诱导对LPS的耐受性对小鼠致死性的保护效果进行评估。
在未处理的小鼠中，用LPS加D-半乳糖胺攻击导致24小时内全部死亡，而仅在接受LPS与D-半乳糖胺联合处理的小鼠肝脏中观察到特征性凋亡DNA片段化。受影响小鼠的死亡率与DNA片段化的发生密切相关。相比之下，在预先接触LPS的小鼠中，用LPS/D-半乳糖胺攻击时，致死效应和凋亡DNA片段化均受到抑制。除LPS外，诱导小鼠对TNF产生耐受性还能使小鼠在存在D-半乳糖胺的情况下受到TNF和/或LPS攻击时，对死亡和凋亡DNA片段化产生交叉反应。此外，LPS的这种保护作用可持续长达24小时。TNFR1而非TNFR2在诱导对LPS的耐受性以保护小鼠免于死亡或诱导导致小鼠死亡的发病过程的信号通路中起双重作用。
D-半乳糖胺处理的小鼠对LPS的死亡率与肝脏凋亡的发生高度相关，通过使小鼠短暂接触微量LPS可有效抑制该凋亡。诱导的耐受状态不仅由LPS介导，也由TNF介导。对LPS或TNF产生的耐受性在LPS和TNF攻击之间可相互交叉反应，而诱导耐受和促进凋亡的信号传导是通过TNFR1，而非TNFR2。
