Chensue S W, Terebuh P D, Remick D G, Scales W E, Kunkel S L
Department of Pathology, Veterans Affairs Medical Center, Ann Arbor, MI 48105.
Am J Pathol. 1991 Feb;138(2):395-402.
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.
作者采用经肠外给予小鼠细菌脂多糖（LPS）诱导脓毒症的模型，分析了白细胞介素-1（IL-1）α、β及肿瘤坏死因子（TNF）的体内表达情况。通过免疫组织化学方法在肝窦巨噬细胞（库普弗细胞）中检测到了TNF以及IL-1α、β。动力学分析显示出清晰的合成顺序。首先产生肿瘤坏死因子，在LPS攻击后1小时达到最大表达，随后迅速消失。接着是IL-1β，在2至3小时达到最大表达，然后在6小时下降。白细胞介素-1α的表达在6小时达到峰值，并在18小时消失。血清生物活性分析也显示出与免疫组织化学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生物活性并非由白细胞介素-6（IL-6）引起，因为通过免疫吸附从标本中去除了IL-6。此外，IL-6生物活性在3小时达到最高水平，早于IL-1。用4mg/kg地塞米松预处理可显著降低库普弗细胞中TNF和IL-1α的表达（分别约抑制80%和60%），但对IL-1β表达的影响较小（约抑制30%）。相应地，血清TNF水平被抑制75%，而血清IL-1降低39%，表明这些细胞因子对糖皮质激素的敏感性不同。随着TNF水平下降，内源性皮质类固醇水平升高，支持了糖皮质激素调节TNF合成的观点。相反，IL-1水平与皮质酮同时升高。这些数据表明体内细胞因子基因表达的顺序激活，这可能对导致脓毒性休克的一系列事件至关重要，并提供证据表明库普弗细胞是内毒素血症中细胞因子的主要来源。最后，细胞因子表达对糖皮质激素的不同敏感性可能部分解释了后者在脓毒症治疗中的不足。
