Tocopherol isoforms (α-, γ-, and δ-) show distinct capacities to control Nrf-2 and NfκB signaling pathways that modulate inflammatory response in Caco-2 intestinal cells

We recently showed that alpha-, gamma-, and delta-tocopherols (Toc) were isoform dependent in modulating an inflammatory response in differentiated human Caco-2 intestinal cells. Here, we aim to investigate the relative capacity of Toc isoforms to modify the stress-activated Nf kappa B and Nrf-2 signaling pathways that regulate the expression of pro-inflammatory cytokines and antioxidant enzymes, respectively, in this well-established in vitro model of the small intestine The modulation of IFN gamma/phorbol myristate acetate (PMA)-induced inflammatory responses, determined by the expression of IL8 mRNA and protein, corresponded to the extent by which different Toc isoforms altered intracellular oxidative status in Caco-2 cells. alpha Toc was more effective at suppressing IFN gamma/PMA-induced Nf kappa B activation than gamma-Toc, while delta-Toc was ineffective. On the other hand, only d-Toc and to a lesser extent gamma-Toc promoted IFN gamma/PMA-induced Nrf-2 activation. Upregulation of Nrf-2 by d-Toc coincided with a decrease in GSH/GSSG ratio, thus pointing to pro-oxidant activity of delta-Toc isoform in IFN gamma/PMA-stimulated Caco-2 cells. The induction of oxidative stress in IFN gamma/PMA-treated cells by delta-Toc was lowered (P < 0.05) in the presence of ascorbic acid. Ascorbic acid also enabled a greater suppression of IL8 secretion than when cells were treated with delta-Toc isoform alone. Our findings show that delta-Toc uniquely promoted oxidative stress which translated to Toc isoform-specific modulation of the stress-activated Nrf-2 and Nf kappa B signaling pathway and an influence on IL8 expression.