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 α-, γ-, and δ-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 NfκB 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 IFNγ/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. α Toc was more effective at suppressing IFNγ/PMA-induced NfκB activation than γ-Toc, while δ-Toc was ineffective. On the other hand, only δ-Toc and to a lesser extent γ-Toc promoted IFNγ/PMA-induced Nrf-2 activation. Up-regulation of Nrf-2 by δ-Toc coincided with a decrease in GSH/GSSG ratio, thus pointing to pro-oxidant activity of δ-Toc isoform in IFNγ/PMA-stimulated Caco-2 cells. The induction of oxidative stress in IFNγ/PMA-treated cells by δ-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 δ-Toc isoform alone. Our findings show that δ-Toc uniquely promoted oxidative stress which translated to Toc isoform-specific modulation of the stress-activated Nrf-2 and NfκB signaling pathway and an influence on IL8 expression.
Food, Nutrition and Health Program, University of British Columbia, 219-2205 East Mall, Vancouver, BC, V6T 1Z4, Canada.
Ingrid
I
Elisia
David D
DD
Kitts
D000975:Antioxidants / Q000494:pharmacology; D018938:Caco-2 Cells; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D020033:Protein Isoforms; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D024505:Tocopherols / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000494:pharmacology; D024504:gamma-Tocopherol / Q000494:pharmacology*
D000975:Antioxidants; C508606:CXCL8 protein, human; D016209:Interleukin-8; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D020033:Protein Isoforms; D017382:Reactive Oxygen Species; D024504:gamma-Tocopherol; D024502:alpha-Tocopherol; C479072:delta-tocopherol; D013755:Tetradecanoylphorbol Acetate; D024505:Tocopherols