The physiological role of AhR, particularly in immune response remains a key question after identification of AhR as an essential transcription factor for Th17 differentiation. Selective AhR modulators (SAhRMs) are a recently identified class of compounds that are capable of binding to AhR and repress cytokine- driven gene expression. These compounds are interesting therapeutically as they can be used to inhibit Dioxin Response Element (DRE)-mediated while inducing anti-inflammatory responses. Under non-skewing conditions, AhR agonist beta-naphthoflavone (BNF) enhances IL-17A production whereas SGA-360 an inhibitor suppresses it. Under Th17 skewing condition, AhR agonist BNF enhanced Th17 differentiation whereas AhR antagonist GNF and partial antagonist SGA-360 suppressed it. Interestingly, under Treg skewing condition the antagonists enhanced the Foxp3 expression, suggesting that such compounds have therapeutic potential in autoimmune disease by modulating the Th17/Treg balance. We have also examined AhR antagonists after disease development in a murine model of Th17 mediated disease, hypersensitivity pneumonitis mediated by Staphylopolyspora rectivirgula (SR). We find that these antagonists suppress AhR activity and induce IL-4, suggestive of a shift in T helper lineage. This suggests that SAhRMs may be useful in modulating AhR activation to regulate Th17/Treg balance, and that AhR selective ligands have potential for use as therapeutics in Th17 mediated diseases.
- Copyright © 2013 by The American Association of Immunologists, Inc.