Wogoniol, a novel radiolytic derivative of wogonin, programs dendritic cells for immune tolerance: suppression of T helper 1/17 and promotion of regulatory T cells.

BACKGROUND: Tolerogenic dendritic cells (tolDCs) play a pivotal role in maintaining immune homeostasis by driving regulatory T cell (Treg) differentiation. Modulating DC phenotypes to restore immune tolerance is a primary therapeutic goal for controlling inflammatory responses. OBJECTIVES: Here, we investigate the immunoregulatory mechanisms of wogoniol, a novel non-planar radiolytic derivative of the phytochemical wogonin featuring a C2-hydroxymethyl group, on DC-T cell crosstalk. METHODS: The immunomodulatory effects of wogoniol were evaluated using lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs) and in vitro DC-T cell co-culture systems. Intracellular signaling mechanisms driving the DC phenotype were analyzed and validated using specific pharmacological inhibitors. RESULTS: In LPS-stimulated bone marrow-derived dendritic cells (BMDCs), the parent wogonin acted as a nonspecific inhibitor, suppressing both pro- (TNF-α and IL-12p70) and anti-inflammatory (IL-10) cytokines. In contrast, wogoniol induced a stable tolDC phenotype, suppressing TNF-α and IL-12p70 while significantly upregulating the anti-inflammatory cytokine IL-10 and immunosuppressive molecule PD-L1. Mechanistically, wogoniol suppressed JNK phosphorylation while activating p38 and STAT3. Pharmacological inhibition confirmed that these pathways are essential for the observed tolerogenic phenotype. In subsequent DC-T cell co-cultures, wogoniol-treated DCs potently suppressed Th1 (T-bet/IFN-γ) and Th17 (RORγt/IL-17A) differentiation while strongly promoting the induction of CD4+CD25+Foxp3+ regulatory T cells (Tregs) to a level comparable to dexamethasone. CONCLUSIONS: Wogoniol exhibits a potent immune skewing mechanism absent in its parent compound, programming DCs to suppress pathogenic Th1/Th17 responses while actively inducing Foxp3+ Tregs. These findings establish wogoniol as a promising new pharmacological candidate for inducing immune tolerance.