Effects of Aryl−Hydrocarbon Ligands on Dendritic Cell Maturation

Abstract

Aryl-hydrocarbon receptor (AhR) is a cytosolic receptor found in many cells, including immune cells, and its function has been implicated in metabolic and transcriptional control of immune regulation. In the present study we have investigated the effect of the AhR-ligands, FICZ, I3C, curcumin, quercetin and the ligands precursor tryptophan, on bone marrow-derived dendritic cell (BMDC) maturation and immuno-stimulatory or immuno-suppressive phenotypes. We find that immature and mature BMDC express intracellular AhR. Treatment of BMDC with AhR-ligands during LPS-induced BMDC maturation had no significant effect on the expression of MHC class II, CD40 and CD86, with the exception of I3C which suppressed CD40 expression by BMDC at high doses. However, all AhR-ligands significantly enhanced the secretion of pro-inflammatory cytokines, including IL-6, IL-12p40, TNF-α, and IL-1β. In contrast, only the AhR-ligands FICZ and I3C increased IL-10 and TGF-β secretion. Tryptophan, curcumin, and quercetin significantly suppressed IL-10 secretion without affecting TGF-β secretion. Finally, FICZ and I3C significantly enhanced the expression of the tolerogenic DC enzyme, indoleamine-2, 3-dioxygenase (IDO), while tryptophan, curcumin and quercetin did not change IDO expression. These results suggest that FICZ and I3C can promote a tolerogenic BMDC phenotype consistent with suppression of immune responses by enhancing the secretion of anti-inflammatory cytokines and increasing IDO expression. In contrast, tryptophan, curcumin and quercetin can promote an immuno-stimulatory BMDC phenotype, secreting elevated pro-inflammatory cytokines, which could help in skewing T cell responses towards the development of effector CD4 and CD8 T cell subsets.