Sulforaphane Protects from T Cell–Mediated Autoimmune Disease by Inhibition of IL-23 and IL-12 in Dendritic Cells

Abstract

Sulforaphane (SFN), an isothiocyanate, is part of an important group of naturally occurring small molecules with anti-inflammatory properties. The published reports are best conceivable with an inhibition of T cell function, but the mode of action remains unknown. We therefore analyzed the effect of SFN on T cell–mediated autoimmune disease. Feeding mice with SFN protected from severe experimental autoimmune encephalomyelitis. Disease amelioration was associated with reduced IL-17 and IFN-γ expression in draining lymph nodes. In vitro, SFN treatment of T cells did not directly alter T cell cytokine secretion. In contrast, SFN treatment of dendritic cells (DCs) inhibited TLR4-induced IL-12 and IL-23 production, and severely suppressed Th1 and Th17 development of T cells primed by SFN-treated DCs. SFN regulated the activity of the TLR4-induced transcription factor NF-κB, without affecting the degradation of its inhibitor IκB-α. Instead, SFN treatment of DCs resulted in strong expression of the stress response protein heme oxygenase-1 (HO-1), which interacts with and thereby inhibits NF-κB p65. Consistent with these findings, HO-1 bound to p65 and subsequently inhibited the p65 activity at the IL23a and IL12b promoters. Importantly, SFN suppressed Il23a and Il12b expression in vivo and silenced Th17/Th1 responses within the CNS. Thus, our data show that SFN improves Th17/Th1-mediated autoimmune disease by inducing HO-1 and inhibiting NF-κB p65-regulated IL-23 and IL-12 expression.

Cholesterol Modification of p40-Specific Small Interfering RNA Enables Therapeutic Targeting of Dendritic Cells

“…Moreover, p40 as target gene/sequence limits unwanted off-target effects. In agreement with the early peak of IL-12 and IL-23 expression after EAE immunization (37) and the previous experience with p40 Ab treatments in MS and EAE (38,39), chol-p40-siRNA treatment also is most potent during early disease states. Thus, delivering chol-p40-siRNA after clinically established EAE had only mild effects.…”

Sulforaphane protects against sodium valproate–induced acute liver injury

“…Meanwhile, SFN has also been reported to be a potent inducer of phase II detoxifying enzymes in vitro and in vivo (Geisel et al 2016;Gerha¨user et al 1997;Hu et al 2002).…”

“…SFN-mediated effects on cellular systems regulating oxidative stress and activation of several cytoprotective genes, is believed to be mediated throughtheNrf2/ARE signaling pathway (Geisel et al 2016) As aNrf2 agonist, SFN induces Nrf2 nuclear localization and antioxidant response elements (ARE) transactivation, enhancing phase II detoxifying enzyme activities and hence free radicals elimination (Guerrero-Beltra´n et al 2012). Nrf2 regulates the transcription of cytoprotective genes promoting cell protection against oxidative damage.…”

“…Nrf2 regulates the transcription of cytoprotective genes promoting cell protection against oxidative damage. SFN directly activates Nrf2, therefore, SFN is considered to be an indirect antioxidant (Geisel et al, 2016). It has further been shown that SFN-induced activation of phase II detoxification is also mediated through the induction of release of Nrf2 from the Keap 1-Nrf2 cytoplasmic complex (Wang et al 2015).…”

The role of IL-4 in psoriasis

“…In humans with psoriasis DMF induces IL-4-producing Th2 cells in peripheral blood and NRF2-regulated genes as well as the Th2 transcription factor GATA3 in skin [29,30]. Interestingly, other compounds like the phytochemical sulforaphane seem to use a similar mode of action as DMF and improve EAE by deviating a Th17 into a Th2 response [31].…”