Activation of Nrf2 skews CD4+ cells toward Th2 differentiation (152.15)

Abstract

Abstract Nuclear erythroid 2 related factor 2 (Nrf2) is a transcription factor activated by cell stress, including oxidative and electrophilic stimuli, resulting in the upregulation of a battery of cytoprotective genes. Although best known for its role in detoxication, Nrf2 has also been shown to have a number of anti-inflammatory effects. The role of Nrf2 in T cells is largely unknown, however. Nrf2 can be activated experimentally by a number of different pharmacological agents, including tert-butylhydroquinone (tBHQ), which is also used commercially as a food preservative. The present studies found that the Nrf2 activator, tBHQ, suppresses production of IFNγ in activated CD4+ cells, while concurrently inducing production of IL-4, IL-5, and IL-13. These effects were also observed in CD4+ cells that were stimulated with anti-CD3/anti-CD28 in the presence tBHQ for 5 days and then restimulated without further addition of Nrf2 activators, suggesting that the effects are due to CD4+ cell differentiation. Furthermore, the current studies suggest that activation of Nrf2 diminishes T-bet binding activity, while concurrently enhancing GATA-3 binding activity. Collectively, the present studies suggest that activation of Nrf2 has a suppressive effect on Th1 differentiation, while promoting Th2 differentiation, which likely occurs through inhibition of T-bet activity and potentiation of GATA-3 activity.