Modulation of NF-κB and Nrf2 control of inflammatory responses in FHs 74 Int cell line is tocopherol isoform-specific

The present study investigates the relative ability of alpha-, gamma-, and delta-tocopherol (Toc) to modulate cell signaling events that are associated with inflammatory responses in fetal-derived intestinal (FHs 74 Int) cells. Secretion of the proinflammatory cytokine IL-8 in FHs 74 Int cells was stimulated in the following order: alpha-Toc < gamma-Toc < delta-Toc. A similar proinflammatory response was observed when inflammation was induced in FHs 74 Int cells. Modulation of IL-8 expression by Toc corresponded to an isoform-specific modulation of NF-kappa B and nuclear factor-erythroid 2-related factor 2 (Nrf2) cell signaling pathways involved in expression of proinflammatory cytokines and antioxidant enzymes, respectively. delta-Toc and, to a lesser extent, gamma-Toc activated NF-kappa B and Nrf2 signaling, as indicated by the greater nuclear translocation of transcription factors. Activation of NF-kappa B signaling by gamma- and delta-Toc was accompanied by upregulation of NF-kappa B target genes, such as IL-8 and prostaglandin-endoperoxide synthase 2, with and without a prior IFN gamma-PMA challenge. Nevertheless, gamma- and delta-Toc, particularly delta-Toc, concurrently downregulated glutamate-cysteine ligase, a Nrf2 target gene that encodes for glutathione biosynthesis. This observation was substantiated by confirmation that gamma- and delta-Toc were effective at decreasing glutamate-cysteine ligase protein expression and cellular glutathione content. Downregulation of glutathione content in fetal intestinal cells corresponded to induction of apoptosis-mediated cytotoxicity. In conclusion, gamma- and delta-Toc are biologically active isoforms of vitamin E and show superior bioactivity to alpha-Toc in modulating cell signaling events that contribute to a proinflammatory response in fetal-derived intestinal cells.