Kim Joo Sung, Jobin Christian
Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
Immunology. 2005 Jul;115(3):375-87. doi: 10.1111/j.1365-2567.2005.02156.x.
The nuclear factor (NF)-kappaB transcriptional system is a major effector pathway involved in inflammation and innate immune responses. The flavonoid luteolin is found in various herbal extracts and has shown anti-inflammatory properties. However, the mechanism of action and impact of luteolin on innate immunity is still unknown. We report that luteolin significantly blocks lipopolysaccharide (LPS)-induced IkappaB phosphorylation/degradation, NF-kappaB transcriptional activity and intercellular adhesion molecule-1 (ICAM-1) gene expression in rat IEC-18 cells. Using chromatin immunoprecipitation, we demonstrate that LPS-induced RelA recruitment to the ICAM-1 gene promoter is significantly reduced in luteolin-treated cells. Moreover, in vitro kinase assays show that luteolin directly inhibits LPS-induced IkappaB kinase (IKK) activity in IEC-18 cells. Using bone-marrow derived dendritic cells (BMDCs) isolated from interleukin (IL)-10(-/-) mice or from recently engineered transgenic mice expressing the enhanced green fluorescent protein (EGFP) under the transcriptional control of NF-kappaB cis-elements (cis-NF-kappaB(EGFP)), we found that luteolin blocks LPS-induced IkappaB phosphorylation and IKK activity, and decreases EGFP, IL-12 and tumour necrosis factor-alpha gene expression. Moreover, intraperitoneal administration of luteolin significantly inhibited LPS-induced EGFP expression in both peripheral blood mononuclear cells and splenocytes isolated from cis-NF-kappaB(EGFP) mice. These results indicate that luteolin blocks LPS-induced NF-kappaB signalling and proinflammatory gene expression in intestinal epithelial cells and dendritic cells. Modulation of innate immunity by natural plant products may represent an attractive strategy to prevent intestinal inflammation associated with dysregulated innate immune responses.
核因子（NF）-κB转录系统是参与炎症和先天免疫反应的主要效应途径。黄酮类化合物木犀草素存在于各种草药提取物中，并已显示出抗炎特性。然而，木犀草素对先天免疫的作用机制和影响仍不清楚。我们报告木犀草素显著阻断脂多糖（LPS）诱导的大鼠IEC-18细胞中IkappaB磷酸化/降解、NF-κB转录活性和细胞间黏附分子-1（ICAM-1）基因表达。使用染色质免疫沉淀法，我们证明在木犀草素处理的细胞中，LPS诱导的RelA募集到ICAM-1基因启动子的现象显著减少。此外，体外激酶分析表明木犀草素直接抑制IEC-18细胞中LPS诱导的IkappaB激酶（IKK）活性。使用从白细胞介素（IL）-10（-/-）小鼠或最近构建的在NF-κB顺式元件（顺式-NF-κB（EGFP））转录控制下表达增强型绿色荧光蛋白（EGFP）的转基因小鼠中分离的骨髓来源树突状细胞（BMDC），我们发现木犀草素阻断LPS诱导的IkappaB磷酸化和IKK活性，并降低EGFP、IL-12和肿瘤坏死因子-α基因表达。此外，腹腔注射木犀草素显著抑制从顺式-NF-κB（EGFP）小鼠分离的外周血单核细胞和脾细胞中LPS诱导的EGFP表达。这些结果表明木犀草素阻断LPS诱导的肠道上皮细胞和树突状细胞中NF-κB信号传导和促炎基因表达。天然植物产物对先天免疫的调节可能是预防与先天免疫反应失调相关的肠道炎症的一种有吸引力的策略。
