Abstract
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.