Acute alcohol inhibits the induction of nuclear regulatory factor κB activation through CD14/toll-Like receptor 4, interleukin-1, and tumor necrosis factor receptors:: A common mechanism independent of inhibitory κBα degradation?
Acute alcohol inhibits the induction of nuclear regulatory factor κB activation through CD14/toll-Like receptor 4, interleukin-1, and tumor necrosis factor receptors:: A common mechanism independent of inhibitory κBα degradation?
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DOI：
10.1097/01.alc.0000036926.46632.57
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发表时间：
2002-11-01
影响因子：
3.2
通讯作者：
Szabo, G
中科院分区：
文献类型：
--
作者：
Mandrekar, P;Dolganiuc, A;Szabo, G
背景资料：核因子κ B（NF-κ B）的核转位和DNA结合是炎症细胞活化中响应细菌组分或细胞因子刺激的早期事件。通过不同受体的细胞活化在导致NF-κ B活化和促炎细胞因子诱导的共同途径中达到高潮。我们以前已经表明，急性酒精抑制NF-κ B激活的脂多糖（LPS）在人单核细胞。在这里，我们调查是否急性酒精治疗的人单核细胞也抑制NF-κ B时，诱导通过激活白细胞介素（IL）-1或肿瘤坏死因子（TNF）receptors.Methods：人外周血单核细胞与LPS，TNF α，IL-1 β在存在或不存在的25 mM酒精1 hr. NF-κ B激活的电泳迁移率变动测定使用核提取物。通过蛋白质印迹法在细胞质提取物中估计抑制性kappaB α（IkappaB α）。表达人CD 14的中国仓鼠卵巢细胞用LPS处理，在存在或不存在酒精的情况下，研究NF-κ B和IkappaBalpha regulation.Results：我们的研究结果表明，急性酒精抑制IL-1 β和TNF α诱导的NF-κ B活化。我们进一步表明，在表达CD 14/toll样受体4的中国仓鼠卵巢细胞中，酒精通过toll样受体4/CD 14受体介导的NF-κ B抑制的特异性。急性酒精对NF-κ B的抑制是伴随着LPS，IL-1和TNF α激活的单核细胞的细胞质中的IkappaBalpha分子水平降低的。结论：这些数据表明，一个独特的，IkappaBalpha独立的途径抑制急性酒精在单核细胞中的NF-κ B激活。急性酒精通过这些不同的受体系统对NF-κ B的普遍抑制表明，酒精在NF-κ B激活级联反应中的作用是IkappaB α降解的下游。此外，这些结果表明，急性酒精是单核细胞中炎症早期（LPS）或晚期（IL-1，TNF α）介质激活NF-κ B的有效抑制剂。
Background: Nuclear translocation and DNA binding of the nuclear factor kappaB (NF-kappaB) is an early event in inflammatory cell activation in response to stimulation with bacterial components or cytokines. Cell activation via different receptors culminates in a common pathway leading to NF-kappaB activation and proinflammatory cytokine induction. We have previously shown that acute alcohol inhibits NF-kappaB activation by lipopolysaccharide (LPS) in human monocytes. Here we investigated whether acute alcohol treatment of human monocytes also inhibits NF-kappaB when induced through activation of the interleukin (IL)-1 or tumor necrosis factor (TNF) receptors.Methods: Human peripheral blood monocytes were treated with LPS, TNFalpha, and IL-1beta in the presence or absence of 25mM alcohol for 1 hr. NF-kappaB activation was determined by electrophoretic mobility shift assays using nuclear extracts. Inhibitory kappaBalpha (IkappaBalpha) was estimated by Western blotting in cytoplasmic extracts. Chinese hamster ovary cells expressing human CD14 were treated with LPS in the presence or absence of alcohol to study NF-kappaB and IkappaBalpha regulation.Results: Our results indicate that acute alcohol inhibits IL-1beta- and TNFalpha-induced NF-kappaB activation. We further show in CD14/toll-like receptor 4-expressing Chinese hamster ovary cells the specificity of alcohol-mediated inhibition of NF-kappaB via the toll-like receptor 4/CD14 receptors. Inhibition of NF-kappaB by acute alcohol was concomitant with decreased levels of the IkappaBalpha molecule in the cytoplasm of LPS, IL-1, and TNFalpha-activated monocytes.Conclusions: These data suggest a unique, IkappaBalpha-independent pathway for the inhibition of NF-kappaB activation by acute alcohol in monocytes. Universal inhibition of NF-kappaB by acute alcohol via these various receptor systems suggests a target for the effects of alcohol in the NF-kappaB activation cascade that is downstream from IkappaBalpha degradation. Further, these results demonstrate that acute alcohol is a potent inhibitor of NF-kappaB activation by mediators of early (LPS) or late (IL-1, TNFalpha) stages of inflammation in monocytes.