Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari, IDIM-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, C1427ARO Buenos Aires, Argentina.
Laboratorio de Biología Molecular y Apoptosis, Instituto de Investigaciones Médicas Alfredo Lanari, IDIM-CONICET, Facultad de Medicina, Universidad de Buenos Aires, Combatientes de Malvinas 3150, C1427ARO Buenos Aires, Argentina ; Argentine National Research Council (CONICET), Argentina.
FEBS Open Bio. 2014 May 2;4:450-7. doi: 10.1016/j.fob.2014.04.009. eCollection 2014.
RAC3 is a coactivator of glucocorticoid receptor and nuclear factor-κB (NF-κB) that is usually over-expressed in tumors and which also has important functions in the immune system. We investigated the role of the inflammatory response in the control of RAC3 expression levels in vivo and in vitro. We found that inflammation regulates RAC3 levels. In mice, sub-lethal doses of lipopolysaccharide induce the increase of RAC3 in spleen and the administration of the synthetic anti-inflammatory glucocorticoid dexamethasone has a similar effect. However, the simultaneous treatment with both stimuli is mutually antagonistic. In vitro stimulation of the HEK293 cell line with tumor necrosis factor (TNF), one of the cytokines induced by lipopolysaccharide, also increases the levels of RAC3 mRNA and protein, which correlates with an enhanced transcription dependent on the RAC3 gene promoter. We found that binding of the transcription factor NF-κB to the RAC3 gene promoter could be responsible for these effects. Our results suggest that increase of RAC3 during the inflammatory response could be a molecular mechanism involved in the control of sensitivity to both pro- and anti-inflammatory stimuli in order to maintain the normal healthy course of the immune response.
RAC3 是糖皮质激素受体和核因子-κB（NF-κB）的共激活因子，通常在肿瘤中过度表达，在免疫系统中也具有重要功能。我们研究了炎症反应在体内和体外控制 RAC3 表达水平中的作用。我们发现炎症调节 RAC3 水平。在小鼠中，亚致死剂量的脂多糖诱导脾中 RAC3 的增加，而合成抗炎糖皮质激素地塞米松的给药具有类似的作用。然而，两种刺激物的同时处理是相互拮抗的。体外用肿瘤坏死因子（TNF）刺激 HEK293 细胞系，TNF 是脂多糖诱导的细胞因子之一，也增加 RAC3 mRNA 和蛋白的水平，这与依赖 RAC3 基因启动子的转录增强相关。我们发现转录因子 NF-κB 与 RAC3 基因启动子的结合可能是这些作用的原因。我们的结果表明，炎症反应期间 RAC3 的增加可能是一种分子机制，参与控制对促炎和抗炎刺激的敏感性，以维持免疫反应的正常健康过程。
