TY - JOUR
T1 - Dietary ligands of the aryl hydrocarbon receptor induce anti-inflammatory and immunoregulatory effects on murine dendritic cells
AU - Benson, Jenna M.
AU - Shepherd, David M.
N1 - Funding Information:
The authors wish to thank the CEHS Fluorescence Cytometry Core and Molecular Biology Core at the University of Montana (supported by the National Institutes of Health grant RR017670) for their support. The authors also thank Drs Celine Beamer, Jerry Smith, and Scott Wetzel for critical review of this manuscript. Drs Earle Adams and Fernando Cardozo-Pelaez are also acknowledged, as they assisted with compound purity and stability analyses. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, NIEHS, or NCCAM.
Funding Information:
This project was supported by the National Institutes of Health grant ES013784 (D.M.S) and by award F31AT005557 (J.M.B.) from the National Center for Complementary and Alternative Medicine (NCCAM).
PY - 2011/12
Y1 - 2011/12
N2 - Activation of the aryl hydrocarbon receptor (AhR) in immune cells, such as dendritic cells (DCs), can lead to suppressed immune responses. Although AhR activation is most recognized for mediating the effects of its prototypical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), many compounds existing in dietary sources can also bind the AhR. Because the immunomodulatory effects of indole-3-carbinol (I3C) and indirubin-3'-oxime (IO) have yet to be investigated in DCs, we evaluated the potential immunomodulatory effects of these compounds on murine DCs. We hypothesized that I3C and IO suppress immune and inflammatory responses in DCs. We found that both I3C and IO decreased the expression of CD11c, CD40, and CD54 while they increased expression of MHC2 and CD80. Following lipopolysaccharide (LPS)-activation, I3C and IO suppressed the production of pro-inflammatory mediators including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-12, and nitric oxide but increased IL-10 levels. These effects of I3C and IO were partially mediated by the AhR. Additionally, immunoregulatory genes, such as ALDH1A, IDO and TGFB, were upregulated following treatment with I3C or IO. Both I3C and IO decreased basal levels of nuclear factor-kappa B p65, but only I3C suppressed the LPS-induced activity of RelB. Finally, when cultured with naïve T cells, bone marrow-derived dendritic cells treated with the dietary AhR ligands increased the frequency of Foxp3+ Tregs in an antigen-specific manner. Taken together, these results indicate that I3C and IO exhibit immunosuppressive and anti-inflammatory effects on DCs. Because I3C and IO are significantly less toxic than TCDD, these natural products may ultimately become useful therapeutics for the treatment of autoimmune and inflammatory diseases.
AB - Activation of the aryl hydrocarbon receptor (AhR) in immune cells, such as dendritic cells (DCs), can lead to suppressed immune responses. Although AhR activation is most recognized for mediating the effects of its prototypical ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), many compounds existing in dietary sources can also bind the AhR. Because the immunomodulatory effects of indole-3-carbinol (I3C) and indirubin-3'-oxime (IO) have yet to be investigated in DCs, we evaluated the potential immunomodulatory effects of these compounds on murine DCs. We hypothesized that I3C and IO suppress immune and inflammatory responses in DCs. We found that both I3C and IO decreased the expression of CD11c, CD40, and CD54 while they increased expression of MHC2 and CD80. Following lipopolysaccharide (LPS)-activation, I3C and IO suppressed the production of pro-inflammatory mediators including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-12, and nitric oxide but increased IL-10 levels. These effects of I3C and IO were partially mediated by the AhR. Additionally, immunoregulatory genes, such as ALDH1A, IDO and TGFB, were upregulated following treatment with I3C or IO. Both I3C and IO decreased basal levels of nuclear factor-kappa B p65, but only I3C suppressed the LPS-induced activity of RelB. Finally, when cultured with naïve T cells, bone marrow-derived dendritic cells treated with the dietary AhR ligands increased the frequency of Foxp3+ Tregs in an antigen-specific manner. Taken together, these results indicate that I3C and IO exhibit immunosuppressive and anti-inflammatory effects on DCs. Because I3C and IO are significantly less toxic than TCDD, these natural products may ultimately become useful therapeutics for the treatment of autoimmune and inflammatory diseases.
KW - Aryl hydrocarbon receptor (AhR)
KW - Dendritic cells (DCs)
KW - Immune modulation
KW - Indirubin
KW - Indole-3-carbinol (I3C)
UR - http://www.scopus.com/inward/record.url?scp=81855199717&partnerID=8YFLogxK
U2 - 10.1093/toxsci/kfr249
DO - 10.1093/toxsci/kfr249
M3 - Article
C2 - 21948866
AN - SCOPUS:81855199717
SN - 1096-6080
VL - 124
SP - 327
EP - 338
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 2
ER -