Department of Pharmacology and Toxicology, Faculty of Medicine, Health and Life Sciences, Maastricht University, PO Box 616, 6200, MD, Maastricht, the Netherlands.
Chem Biol Interact. 2018 Aug 1;291:237-244. doi: 10.1016/j.cbi.2018.06.024. Epub 2018 Jun 21.
Chronic inflammation and oxidative stress are (sub)cellular processes that enhance each other and contribute to the genesis of many systemic pathologies. The endogenous glucocorticoid cortisol plays an important role in the physiological termination of a pro-inflammatory immune response. However, in conditions of pronounced oxidative stress the anti-inflammatory action of cortisol is impaired. Since grape seed-derived monomeric and oligomeric flavan-3-ols (MOF) have been shown to attenuate both inflammation and oxidative stress in vitro and in humans, we hypothesized that these compounds are able to maintain the anti-inflammatory activity of cortisol in immune cells in a pro-oxidant environment. In a glucocorticoid resistance model using human monocytes (THP-1 cell line) differentiated into macrophage-like cells we observed that exposure to 1 mM tertiary butyl hydroperoxide (t-BuOOH) for 4 h significantly hampered the anti-inflammatory action of cortisol assessed as attenuation of the interleukin (IL)-8 production. Under these conditions, the effects of MOF were assessed on pro-inflammatory cytokines expression, cortisol's anti-inflammatory action and on the expression of 11β-hydroxysteroid dehydrogenase (11β-HSD) 1, which catalyzes intracellular conversion of cortisone to cortisol. MOF attenuated the gene expression of pro-inflammatory cytokines and prevented the decline of the anti-inflammatory effect of cortisol in the presence of t-BuOOH. MOF also maintained the activity of histone deacetylase in the cell nucleus which is essential for cortisol's molecular action to terminate the transcription of pro-inflammatory genes. Moreover, MOF prevented the down-regulation of 11β-HSD1 gene expression in this pro-oxidant cellular environment. Taken together our data suggest that MOF contribute to maintain the anti-inflammatory action of cortisol under pro-oxidant conditions via preservation of the intracellular availability of bioactive cortisol and cortisol-mediated termination of pro-inflammatory gene transcription. These findings provide novel insights in how MOF may enhance the ability to adapt, which is of particular relevance for their rational use as dietary supplement to maintain health.
慢性炎症和氧化应激是相互增强的（亚）细胞过程，导致许多全身性疾病的发生。内源性糖皮质激素皮质醇在炎症性免疫反应的生理终止中起着重要作用。然而，在明显氧化应激的情况下，皮质醇的抗炎作用受损。由于葡萄种子来源的单体和低聚黄烷-3-醇（MOF）已被证明可以在体外和人体中减轻炎症和氧化应激，我们假设这些化合物能够在促氧化剂环境中维持皮质醇在免疫细胞中的抗炎活性。在使用人单核细胞（THP-1 细胞系）分化为巨噬细胞样细胞的糖皮质激素抵抗模型中，我们观察到暴露于 1mM 叔丁基过氧化物（t-BuOOH）4 小时显著阻碍了皮质醇的抗炎作用，评估为白细胞介素（IL）-8 产生的减弱。在这些条件下，评估了 MOF 对促炎细胞因子表达、皮质醇抗炎作用以及 11β-羟类固醇脱氢酶（11β-HSD）1 表达的影响，11β-HSD1 催化细胞内可的松向皮质醇的转化。MOF 减弱了促炎细胞因子的基因表达，并在 t-BuOOH 存在的情况下防止了皮质醇抗炎作用的下降。MOF 还维持了细胞核内组蛋白去乙酰化酶的活性，这对于皮质醇终止促炎基因转录的分子作用至关重要。此外，MOF 防止了在这种促氧化剂细胞环境中 11β-HSD1 基因表达的下调。总之，我们的数据表明，MOF 通过维持细胞内生物活性皮质醇的可用性和皮质醇介导的促炎基因转录终止，有助于在促氧化剂条件下维持皮质醇的抗炎作用。这些发现为 MOF 如何增强适应能力提供了新的见解，这对于将其作为膳食补充剂合理使用以维持健康具有特别重要的意义。
