Expression of cytokines and activation of transcription factors in lipopolysaccharide-administered rats and their inhibition by phenyl N-tert-butylnitrone (PBN).
Expression of cytokines and activation of transcription factors in lipopolysaccharide-administered rats and their inhibition by phenyl N-tert-butylnitrone (PBN).
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DOI：
10.1006/abbi.1998.1086
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发表时间：
1999-03
影响因子：
3.9
通讯作者：
H. Sang;G. Wallis;C. Stewart;Y. Kotake
中科院分区：
文献类型：
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作者：
H. Sang;G. Wallis;C. Stewart;Y. Kotake
自旋捕获化合物苯基N-叔丁基硝酮（PBN）可保护啮齿类动物免于感染性休克的致死性。以往的研究表明PBN通过抑制诱导型一氧化氮合酶（iNOS）的诱导而发挥其保护作用。本研究利用脂多糖（LPS）诱导的大鼠感染性休克模型，检测了各种细胞因子基因的表达（肿瘤坏死因子（TNF）-α，TNF-β，干扰素（IFN）-γ，白细胞介素（IL）-1 α，IL-1 β，IL-2，IL-3，IL-4，IL-5，IL-6，和IL-10）以及肝组织中转录因子核因子-κ B（NF-κ B）和激活蛋白-1（AP-1）的活化。还研究了PBN预给药对产量水平的影响。结果表明，LPS（4 mg/kg，ip）在30 min内诱导了细胞因子基因的产生，并增加了NF-κ B核蛋白水平。PBN（150 mg/kg，ip）预处理可显著下调LPS注射后3 h细胞因子基因的产生（TNF-α降低94%，IL-1降低63%，IL-1降低70%），并使NF-κ B和AP-1的核蛋白水平分别降低75%和72%。这些结果表明，PBN，除了其诱导型一氧化氮合酶的抑制，也有多种抗炎作用，在脓毒性休克，通过调制的关键炎症介质的产生。
The spin-trapping compound phenyl N-tert-butylnitrone (PBN) affords protection from the lethality of septic shock in rodents. Previous studies have shown that PBN elicits its protection by inhibiting inducible nitric oxide synthase (iNOS) induction. In the present study, using the lipopolysaccharide (LPS) rat septic shock model, we determined the expression of various cytokine genes (tumor necrosis factor (TNF)-alpha, TNF-beta, interferon (IFN)-gamma, interleukin (IL)-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, and IL-10) and the activation of transcription factors nuclear factor kappaB (NF-kappaB) and activator protein-1 (AP-1) in the liver tissue, 30 min and 3 h after LPS administration. The effects of PBN preadministration on the production levels were also investigated. The results show that LPS (4 mg/kg, ip) induced the production of the cytokine genes and increased the nuclear protein level of NF-kappaB within 30 min after LPS administration. Preadministration of PBN (150 mg/kg, ip) significantly down-regulated the production of cytokine genes (TNF-alpha by 94%, IL-1 by 63%, and IL-1 by 70%) and reduced the nuclear protein level of NF-kappaB by 75% and AP-1 by 72% at 3 h after LPS injection. These results demonstrate that PBN, in addition to its iNOS induction inhibition, also has multiple anti-inflammatory effects in septic shock, via modulation of the production of the key inflammatory mediators.