Luster M I, Germolec D R, Yoshida T, Kayama F, Thompson M
Environmental Immunology and Neurobiology Section, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Hepatology. 1994 Feb;19(2):480-8.
Peptide mediators, including tumor necrosis factor-alpha, interleukin 1 and interleukin-6, are associated with many chronic inflammatory diseases and septic shock. As such, considerable information has been collected by means of study of cytokine secretion from isolated cells or plasma cytokines during septic shock or inflammatory disorders. In this investigation, we used semiquantitative polymerase chain reaction analysis and a recently developed liver slice model to examine the characteristics of cytokine profiles that occur in the liver, the main organ involved in endotoxemia, after lipopolysaccharide challenge. Tumor necrosis factor-alpha, interleukin-1 alpha and interleukin-6 were rapidly secreted after in vivo LPS exposure or when added in vitro to rodent or human liver slice samples. This increase was associated with increased cytokine-specific mRNA transcripts. Kinetic analysis revealed that most tumor necrosis factor-alpha is released from the liver within 1 hr of lipopolysaccharide challenge, whereas interleukin-1 alpha and interleukin-6 continued to be produced for the entire culture period. Addition of monoclonal antibodies against tumor necrosis factor-alpha or interleukin-1 alpha to the culture partly inhibited interleukin-6 secretion, indicating that interleukin-1 alpha and tumor necrosis factor-alpha help mediate and sustain interleukin-6 synthesis. Depletion of hepatic sinusoidal macrophages (Kupffer cells) by a liposome-mediated macrophage "suicide" technique indicated that almost all of the secreted interleukin-1 alpha and tumor necrosis factor-alpha originate from these cells, whereas interleukin-6 secretion might also include other cell types. This study supports and extends previous findings and allows for a more rational approach to developing effective therapies against chronic inflammatory diseases and septic shock.
包括肿瘤坏死因子-α、白细胞介素1和白细胞介素-6在内的肽类介质与许多慢性炎症性疾病和脓毒性休克有关。因此，通过研究脓毒性休克或炎症性疾病期间分离细胞分泌的细胞因子或血浆细胞因子，已经收集了大量信息。在本研究中，我们使用半定量聚合酶链反应分析和最近开发的肝切片模型，来检查在脂多糖攻击后，肝脏（内毒素血症的主要受累器官）中出现的细胞因子谱特征。在体内暴露于脂多糖后，或者在体外将其添加到啮齿动物或人类肝切片样本中后，肿瘤坏死因子-α、白细胞介素-1α和白细胞介素-6会迅速分泌。这种增加与细胞因子特异性mRNA转录本的增加有关。动力学分析显示，大多数肿瘤坏死因子-α在脂多糖攻击后1小时内从肝脏释放，而白细胞介素-1α和白细胞介素-6在整个培养期间持续产生。向培养物中添加抗肿瘤坏死因子-α或白细胞介素-1α的单克隆抗体，部分抑制了白细胞介素-6的分泌，表明白细胞介素-1α和肿瘤坏死因子-α有助于介导和维持白细胞介素-6的合成。通过脂质体介导的巨噬细胞“自杀”技术清除肝窦巨噬细胞（库普弗细胞）表明，几乎所有分泌的白细胞介素-1α和肿瘤坏死因子-α都来源于这些细胞，而白细胞介素-6的分泌可能还包括其他细胞类型。本研究支持并扩展了先前的发现，并为开发针对慢性炎症性疾病和脓毒性休克的有效疗法提供了更合理的方法。
