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Monomeric and oligomeric flavanols maintain the endogenous glucocorticoid response in human macrophages in pro-oxidant conditions in vitro
Chemico-Biological Interactions ( IF 5.1 ) Pub Date : 2018-06-21 , DOI: 10.1016/j.cbi.2018.06.024
Gesiele Veríssimo , Aalt Bast , Antje R. Weseler

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.



中文翻译:

单体和低聚黄烷醇在体外促氧化剂条件下维持人巨噬细胞的内源性糖皮质激素反应

慢性炎症和氧化应激是相互促进的(亚)细胞过程,并有助于许多系统病理的发生。内源性糖皮质激素皮质醇在促炎性免疫应答的生理终止中起重要作用。但是,在明显的氧化应激条件下,皮质醇的抗炎作用受到损害。由于已经显示葡萄籽衍生的单体和低聚黄烷-3-醇(MOF)在体外和人类中都能减轻炎症和氧化应激,因此我们假设这些化合物能够在免疫中维持皮质醇的抗炎活性。细胞在促氧化剂环境中。

在使用人类单核细胞(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1 mM叔丁基过氧化氢(t -BuOOH)4 h显着阻碍了皮质醇的抗炎作用,据评估降低白介素(IL)-8的产生。

在这些条件下,评估了MOF对促炎性细胞因子表达,皮质醇的抗炎作用以及11β-羟类固醇脱氢酶(11β-HSD)1的表达的作用,催化催化可的松向皮质醇的细胞内转化。

在存在t- BuOOH的情况下,MOF减弱了促炎细胞因子的基因表达并防止了皮质醇的抗炎作用的下降。MOF还保持了细胞核中组蛋白脱乙酰基酶的活性,这对于皮质醇的分子功能终止促炎基因的转录至关重要。此外,MOF阻止了在这种促氧化剂细胞环境中11β-HSD1基因表达的下调。

综上所述,我们的数据表明,MOF通过保持生物活性皮质醇的细胞内可用性和皮质醇介导的促炎性基因转录终止来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颖的见解,这与合理使用其作为维持健康的膳食补充剂特别相关。

更新日期:2018-06-21
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