Dominant negative down-regulation of endotoxin-induced tumor necrosis factor alpha production by Lps(d)/Ran.
Dominant negative down-regulation of endotoxin-induced tumor necrosis factor alpha production by Lps(d)/Ran.
复制标题
Lps(d)/Ran 对内毒素诱导的肿瘤坏死因子 α 产生显着负下调。
DOI：
10.1073/pnas.040567797
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发表时间：
2000
影响因子：
11.1
通讯作者：
Wong,PM
中科院分区：
文献类型：
--
作者：
Yuan,Q;Zhao,F;Chung,SW;Fan,P;Sultzer,BM;Kan,YW;Wong,PM
我们最近发现，腺病毒转移和表达的Lpsd/Ran基因分离自内毒素抵抗C3 H/HeJ小鼠可以保护内毒素敏感小鼠免受内毒素休克。促炎性细胞因子如肿瘤坏死因子α（TNF-α）的升高被认为是脓毒性休克发展的必要条件。为了研究Lpsd/RancDNA对TNF-α产生的影响程度，我们用表达野生型和突变型Lpsd/RancDNA及其它对照基因的腺病毒载体转导内毒素敏感和耐药小鼠的原代巨噬细胞，并比较这些不同转导的巨噬细胞产生TNF-α的量。 与用表达野生型Lpsn/RancDNA、绿色荧光蛋白基因或lacZ基因的载体转导的巨噬细胞相比，内毒素敏感的C3 H/HeOuJ巨噬细胞中Lpsd/RancDNA的成功转移和表达减少了脂多糖（LPS）刺激时TNF-α的产生。另一方面，野生型Lpsn/RancDNA在来自内毒素抗性C3 H/HeJ小鼠的原代巨噬细胞中的成功转移和表达未能在任何显著程度上诱导TNF-α产生，除非使用非常高的LPS浓度。鉴于我们先前的研究表明Lpsn/Ran能有效地恢复C3 H/HeJ小鼠B细胞对LPS的反应性，我们认为Lpsn/Ran参与了一个不依赖于CD 14的信号转导途径。Lpsd/Ranon对巨噬细胞产生TNF-α的负性负调节以及其他先天性免疫反应可能是开发有效的内毒素或感染性休克基因治疗的关键。
We recently showed that adenoviral transfer and expression of theLpsd/Ran gene isolated from endotoxin-resistant C3H/HeJ mice could protect endotoxin-sensitive mice from endotoxic shock. Elevation of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), is thought to be essential for the development of septic shock. To investigate the extent to whichLpsd/Ranaffects TNF-α production, we transduced primary macrophages from endotoxin-sensitive and -resistant mice with adenoviral vectors expressing the wild-type and the mutantLps/RancDNAs and other control genes, and compared the amount of TNF-α produced by these various transduced macrophages. Successful transfer and expression ofLpsd/RancDNA in endotoxin-sensitive C3H/HeOuJ macrophages reduced TNF-α production upon lipopolysaccharide (LPS) stimulation, as compared with macrophages transduced with vectors expressing the wild-typeLpsn/RancDNA, the green fluorescent protein gene, or thelacZgene. On the other hand, successful transfer and expression of the wild-typeLpsn/RancDNA in primary macrophages from endotoxin-resistant C3H/HeJ mice failed to induce TNF-α production to any significant extent unless a very high LPS concentration was used. Given our previous demonstration that Lpsn/Ran functions effectively in restoring LPS responsiveness in B cells from C3H/HeJ mice, we conclude thatLps/Ranis involved in a CD14-independent signal transduction pathway. This dominant negative down-regulation byLpsd/Ranon TNF-α production by macrophages and probably other innate immune responses may be key to the development of an effective gene therapy for endotoxic or septic shock.