A Holistic Workflow Provides Mechanistic Information into Flavonoid Modulation of Immune Response via Aryl Hydrocarbon Pathways

A holistic workflow integrating in silico analysis with biological validation was developed for investigating flavonoid-mediated immune regulation through aryl hydrocarbon receptor (AHR) pathways. Kaempferol, quercetin, and taxifolin served as the test compounds. Computational modeling indicated structural differences among these flavonoids but similar AHR-binding affinities. In vitro studies using mouse J774A.1 macrophages and human THP-1 monocytes/macrophages revealed kaempferol to be the most effective in inhibiting cell growth and reducing LPS-induced IL-6 mRNA expression. Flavonoid effects were both cell-type and AHR dependent. Overall, our holistic mechanistic workflow demonstrates that attributing specific biological activities to individual flavonoids is highly complex. Factors such as the compound structure, target cell type, and interactions with the aryl hydrocarbon receptor contribute to this complexity. Furthermore, only certain flavonoids appear to engage the aryl hydrocarbon receptor to modulate the immune pathways. Overall, our workflow is useful for elucidating the AHR-related biological efficacies of compounds.