In vivo biologic and immunohistochemical analysis of interleukin-1 alpha, beta and tumor necrosis factor during experimental endotoxemia. Kinetics, Kupffer cell expression, and glucocorticoid effects.
In vivo biologic and immunohistochemical analysis of interleukin-1 alpha, beta and tumor necrosis factor during experimental endotoxemia. Kinetics, Kupffer cell expression, and glucocorticoid effects.
复制标题
DOI：
--
复制
发表时间：
1991-02
期刊：
影响因子：
--
通讯作者：
S. Chensue;D. Pauline;Terebuh;D. Remick;W. Scales;Steven L. Kunkelt
中科院分区：
文献类型：
--
作者：
S. Chensue;D. Pauline;Terebuh;D. Remick;W. Scales;Steven L. Kunkelt
使用细菌脂多糖（LPS）胃肠外激发小鼠诱导的脓毒症模型，作者分析了白细胞介素-1（IL-1）α、β和肿瘤坏死因子（TNF）的体内表达。在肝窦巨噬细胞（枯否细胞）中检测到TNF和IL-1 α，β。动力学分析表明，一个明确的合成顺序。肿瘤坏死因子首先产生，在LPS刺激后1h达到最高表达，然后迅速消失。随后是IL-1 β，在2 - 3小时达到最大表达，然后在6小时下降。白细胞介素-1 α表达在6小时达到峰值，并在18小时消失。血清生物活性分析也揭示了与免疫组化结果相关的顺序表达。肿瘤坏死因子在1小时达到最大值，IL-1在6小时达到最大值。IL-1的生物活性不是由于白细胞介素-6（IL-6），因为其通过免疫吸附从标本中耗尽。IL-6生物活性在3小时达到最大水平，早于IL-1。用4 mg/kg地塞米松预处理显著降低库普弗细胞的TNF和IL-1 α表达（分别约80%和60%抑制），但对IL-1 β表达的影响较小（约30%抑制）。相应地，血清TNF水平被抑制了75%，而血清IL-1降低了39%，表明这些细胞因子对糖皮质激素的敏感性不同。内源性皮质类固醇水平随着TNF水平的降低而增加，支持糖皮质激素调节TNF合成的论点。相反，IL-1水平与皮质酮同时升高。这些数据表明，细胞因子基因表达在体内的顺序激活，这可能是至关重要的级联事件，导致脓毒性休克，并提供证据表明，枯否细胞是内毒素血症的细胞因子的主要来源。最后，细胞因子表达对糖皮质激素的敏感性差异可能部分解释了后者在脓毒症治疗中的不足。
Using a model of sepsis induced by parenteral challenge of mice with bacterial lipopolysaccharide (LPS), the authors analyzed the in vivo expression of interleukin-1 (IL-1) alpha,beta and tumor necrosis factor (TNF). Both TNF and IL-1 alpha,beta were detected in hepatic sinusoidal macrophages (Kupffer cells), immunohistochemically. Kinetic analysis showed a clear sequence of synthesis. Tumor necrosis factor was produced first, reaching maximal expression at 1 hour after LPS challenge, then rapidly disappeared. IL-1 beta followed, reaching maximal expression at 2 to 3 hours, then dropped off by 6 hours. Interleukin-1 alpha expression reached a peak at 6 hours and had disappeared by 18 hours. Analysis of serum bioactivity also revealed sequential expression that correlated with immunohistochemical findings. Tumor necrosis factor was maximal at 1 hour and IL-1 at 6 hours. The IL-1 bioactivity was not due to interleukin-6 (IL-6), as this was depleted from specimens by immunoabsorption. Also IL-6 bioactivity reached maximal levels at 3 hours, earlier than IL-1. Pretreatment with 4 mg/kg dexamethasone significantly decreased Kupffer cell expression of TNF and IL-1 alpha (about 80% and 60% suppression, respectively) but had less effect on IL-1 beta expression (about 30% suppression). Accordingly, serum levels of TNF were suppressed by 75% while serum IL-1 was decreased by 39%, indicating differential sensitivity of these cytokines to glucocorticoids. Endogenous corticosteroid levels increased as TNF levels decreased, supporting the contention that glucocorticoids regulate TNF synthesis. In contrast, IL-1 levels rose concurrently with corticosterone. These data indicate a sequential activation of cytokine gene expression in vivo, which may be critical to the cascade of events leading to septic shock, and provide evidence that Kupffer cells are a major source of cytokines in endotoxemia. Finally, the differential sensitivity of cytokine expression to glucocorticoids may in part explain the inadequacy of the latter in the treatment of sepsis.