Beck G C, Rafat N, Brinkkoetter P, Hanusch C, Schulte J, Haak M, van Ackern K, van der Woude F J, Yard B A
Institute of Anaesthesiology and Critical Care Medicine, University of Mannheim, Theodor-Kutzer Ufer 1-3, 68167 Mannheim, Germany.
Clin Exp Immunol. 2006 Mar;143(3):523-33. doi: 10.1111/j.1365-2249.2006.03005.x.
Interindividual differences of endothelial cells in response to endotoxins might contribute to the diversity in clinical outcome among septic patients. The present study was conducted to test the hypothesis that endothelial cells (EC) with high and low proinflammatory potential exist and to dissect the molecular basis underlying this phenomenon. Thirty human umbilical vein endothelial cell (HUVEC) lines were stimulated for 24 h with lipopolysaccharide (LPS) and screened for interleukin (IL)-8 production. Based on IL-8 production five low and five high producers, tentatively called types I and II responders, respectively, were selected for genome-wide gene expression profiling. From the 74 genes that were modulated by LPS in all type II responders, 33 genes were not influenced in type I responders. Among the 41 genes that were increased in both responders, 17 were expressed significantly stronger in type II responders. Apart from IL-8, significant differences in the expression of proinflammatory related genes between types I and II responders were found for adhesion molecules [intercellular adhesion molecule (ICAM-1), E-selectin)], chemokines [monocyte chemoattractant protein (MCP-1), granulocyte chemotactic protein (GCP-2)], cytokines (IL-6) and the transcription factor CCAAT/enhancer binding protein-delta (C/EBP-delta). Type I responders also displayed a low response towards tumour necrosis factor (TNF)-alpha. In general, maximal activation of nuclear factor (NF)-kappaB was achieved in type I responders at higher concentrations of LPS compared to type II responders. In the present study we demonstrate that LPS-mediated gene expression differs quantitatively and qualitatively in types I and II responders. Our results suggest a pivotal role for common transcription factors as a low inflammatory response was also observed after TNF-alpha stimulation. Further studies are required to elucidate the relevance of these findings in terms of clinical outcome in septic patients.
内皮细胞对内毒素反应的个体差异可能导致脓毒症患者临床结局的多样性。本研究旨在验证存在具有高促炎潜力和低促炎潜力的内皮细胞这一假设，并剖析这一现象背后的分子基础。用脂多糖（LPS）刺激30个人脐静脉内皮细胞（HUVEC）系24小时，并筛选白细胞介素（IL）-8的产生情况。基于IL-8的产生情况，分别选择了5个低产生者和5个高产生者，暂称为I型和II型反应者，进行全基因组基因表达谱分析。在所有II型反应者中受LPS调节的74个基因中，有33个基因在I型反应者中未受影响。在两个反应者中均增加的41个基因中，有17个在II型反应者中表达明显更强。除IL-8外，I型和II型反应者之间在促炎相关基因的表达上存在显著差异，这些基因包括黏附分子[细胞间黏附分子（ICAM-1）、E-选择素]、趋化因子[单核细胞趋化蛋白（MCP-1）、粒细胞趋化蛋白（GCP-2）]、细胞因子（IL-6）和转录因子CCAAT/增强子结合蛋白δ（C/EBP-δ）。I型反应者对肿瘤坏死因子（TNF）-α也表现出低反应。一般来说，与II型反应者相比，I型反应者在更高浓度的LPS下实现了核因子（NF）-κB的最大激活。在本研究中，我们证明LPS介导的基因表达在I型和II型反应者中在数量和质量上存在差异。我们的结果表明常见转录因子起关键作用，因为在TNF-α刺激后也观察到低炎症反应。需要进一步研究以阐明这些发现与脓毒症患者临床结局的相关性。
