Open Collections

Abstract

Vitamin (vit) E comprises 8 isoforms, of which only α-tocopherol (Toc) has been thoroughly investigated. Other vit E isoforms, particularly γ-Toc and δ-Toc, however are present in significant amounts in the North American diet. The effect of α-Toc, γ-Toc and δ-Toc in modulating oxidative status and inflammatory responses in adult-derived Caco-2 and fetal-derived FHs 74 Int intestinal cell lines were thus determined. Toc isoforms were effective antioxidants that protected against peroxyl radical-induced membrane oxidation in both cell lines in an isoform-dependent manner (δ-Toc>γ-To>α-Toc). Nevertheless, Toc isoforms exhibited differential modulation of inflammatory response in the two cell lines, in that Toc isoforms suppressed IFNγ/PMA-induced IL8 expression in Caco-2 cells, but promoted an inflammatory response in FHs 74 Int cells. Modulation of IL8 expression by Toc isoforms corresponded with an efficacy of Toc to modulate NfκB pro-inflammatory and Nrf-2 antioxidant enzyme signaling pathways. Non-α-Toc isoforms promoted Nrf-2 activation in both cell lines. Alpha-Toc and γ-Toc mitigated IFNγ/PMA-induced NfκB activation in Caco-2 cells while non-α-Toc isoforms promoted NfκB activation in FHs 74 Int cells. The pro-oxidant activity of δ-Toc corresponded to its lower ability to suppress IFNγ/PMA-induced IL8 expression and NfκB activation, but enhanced the Nrf-2 signal in Caco-2 cells. One key difference between the effect of Toc isoforms on modulation of NfκB and Nrf-2 signaling was that non-α-Toc isoforms down-regulated the gene expression of glutamate cysteine ligase, the rate-limiting enzyme in glutathione biosynthesis, in FHs 74 Int, but not in Caco-2 cells. This was supported by a reduced (P<0.05) glutathione content in FHs 74 Int cells after incubation with γ-Toc and δ-Toc that was not observed in Caco-2 cells. Downregulation of the glutathione content corresponded to the finding that non-α-Toc isoforms can induce apoptosis-mediated cytotoxicity in FHs 74 Int, but not in Caco-2 cells. Taken together, Toc isoform-mediated modulation of the inflammatory response was not related to antioxidant activity, but rather was attributed to a cell-specific efficacy to modulate NfκB signaling that corresponded to depletion in glutathione content and apoptosis. Based on the current findings, non-α-Toc isoforms are biologically active forms of vit E and their effects on intestinal cells should not be overlooked.