Objective: We previously demonstrated that a high dose of alpha-tocopheryl succinate inhibits interleukin-2 (IL-2) mRNA and production in autoimmune-prone MRL/lpr mice. In the present study, we investigated the regulation of alpha-tocopherol (alphaTOC) on IL-2 gene expression by examining the mRNA of IL-2, inhibitor kappaBalpha (IkappaBalpha), and peroxisome proliferator-activated receptor-gamma (PPARgamma).
Methods: Messenger RNA expression in active splenocytes of BALB/c mice was investigated with reverse transcriptase polymerase chain reaction.
Results: Levels of IL-2 mRNA in phorbol 12-myristate 13-acetate/ionomycin activated splenocytes and cytokine in T-helper-1 cells were increased by 50 microM of alphaTOC but decreased by 1 mM of alphaTOC. In addition, the IkappaBalpha gene expression significantly increased by the high dose (>or=500 microM) of alphaTOC, suggesting an inhibition on nuclear factor-kappaB pathway for activation of IL-2 expression. PPARgamma mRNA level in activated splenocytes was upregulated by 1 mM of alphaTOC. PPARgamma mRNA level in unstimulated splenocytes was upregulated by alphaTOC in a dose-dependent manner, suggesting that alphaTOC might enhance the PPARgamma signaling pathway. High-dose alphaTOC induced apoptosis of splenocytes and inhibited phytohemagglutinin-stimulated T-cell proliferation. Conversely, the proliferative response of splenocytes was enhanced by 5 microM of alphaTOC. Low-dose (50 microM) alphaTOC increased IL-2 expression, which may have been due to the absence of downregulation of PPARgamma and IkappaBalpha on the IL-2 gene.
Conclusion: The results indicated that low and high doses of alphaTOC exert opposite effects on IL-2, possibly through modulation of PPARgamma, IkappaBalpha, and apoptosis pathways. The present findings support our previous observation of opposite effects of low- and high-dose vitamin E on survival of MRL/lpr mice.