Endotoxin preconditioning protects against the cytotoxic effects of TNFalpha after stroke: a novel role for TNFalpha in LPS-ischemic tolerance.
Endotoxin preconditioning protects against the cytotoxic effects of TNFalpha after stroke: a novel role for TNFalpha in LPS-ischemic tolerance.
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发表时间：
2007
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通讯作者：
H. Rosenzweig;M. Minami;Nikola S. Lessov;S. Coste;S. L. Stevens;D. Henshall;R. Meller;R. Simon;M. Stenzel-Poore
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作者：
H. Rosenzweig;M. Minami;Nikola S. Lessov;S. Coste;S. L. Stevens;D. Henshall;R. Meller;R. Simon;M. Stenzel-Poore
脂多糖（LPS）预处理对随后的脑缺血损伤提供神经保护。肿瘤坏死因子-α（TNF-α）在LPS诱导的预处理中具有保护作用，但在缺血中加重神经元损伤。在这里，我们定义的双重作用TNF α在LPS诱导的缺血耐受性在小鼠模型中的中风和在体外原代神经元培养，并表明，TNF α的细胞毒性作用减弱LPS预处理。我们发现LPS预处理显著增加小鼠大脑中动脉闭塞前TNF α的循环水平，并表明TNF α是建立随后的缺血神经保护所必需的，因为缺乏TNF α的小鼠不能通过LPS预处理免受缺血损伤。中风后，LPS预处理的小鼠TNF α（约三倍）和近端TNF α信号分子、神经元TNF受体1（TNFR 1）和TNFR相关死亡结构域（TRADD）的水平显著降低。LPS预处理小鼠中风后可溶性TNFR 1（s-TNFR 1）水平显著增加（约2.5倍），这可能中和TNF α的作用并减少TNF α介导的缺血损伤。重要的是，LPS预处理的小鼠对中风后脑内给予外源性TNF α引起的脑损伤显示出显著的抵抗力。我们在原代皮质神经元培养物中建立了LPS预处理的体外模型，并表明LPS预处理在缺血环境中对损伤性TNFalpha产生显着的保护作用。我们的研究表明，TNF α是一把双刃剑，在中风的设置：TNF α上调是需要建立LPS诱导的耐受缺血前，而抑制TNF α信号在缺血过程中赋予LPS预处理后的神经保护。
Lipopolysaccharide (LPS) preconditioning provides neuroprotection against subsequent cerebral ischemic injury. Tumor necrosis factor-alpha (TNFalpha) is protective in LPS-induced preconditioning yet exacerbates neuronal injury in ischemia. Here, we define dual roles of TNFalpha in LPS-induced ischemic tolerance in a murine model of stroke and in primary neuronal cultures in vitro, and show that the cytotoxic effects of TNFalpha are attenuated by LPS preconditioning. We show that LPS preconditioning significantly increases circulating levels of TNFalpha before middle cerebral artery occlusion in mice and show that TNFalpha is required to establish subsequent neuroprotection against ischemia, as mice lacking TNFalpha are not protected from ischemic injury by LPS preconditioning. After stroke, LPS preconditioned mice have a significant reduction in the levels of TNFalpha (approximately threefold) and the proximal TNFalpha signaling molecules, neuronal TNF-receptor 1 (TNFR1), and TNFR-associated death domain (TRADD). Soluble TNFR1 (s-TNFR1) levels were significantly increased after stroke in LPS-preconditioned mice (approximately 2.5-fold), which may neutralize the effect of TNFalpha and reduce TNFalpha-mediated injury in ischemia. Importantly, LPS-preconditioned mice show marked resistance to brain injury caused by intracerebral administration of exogenous TNFalpha after stroke. We establish an in vitro model of LPS preconditioning in primary cortical neuronal cultures and show that LPS preconditioning causes significant protection against injurious TNFalpha in the setting of ischemia. Our studies suggest that TNFalpha is a twin-edged sword in the setting of stroke: TNFalpha upregulation is needed to establish LPS-induced tolerance before ischemia, whereas suppression of TNFalpha signaling during ischemia confers neuroprotection after LPS preconditioning.