Nobiletin, a polymethoxylated flavonoid from citrus, enhances IL-4 production in DO11.10 mice via antigen-presenting cells.

Abstract

The polymethoxylated flavonoid nobiletin has been shown to have a broad range of biological functions. We found that nobiletin regulates cytokine production from T cells. In this study, we examined the mechanism for enhancement of interleukin (IL)-4 production by nobiletin. We investigated the key molecules for production of IL-4 by deep data-based analysis and we identified nine candidate genes. The mRNA expression levels of c-Maf, Gata-3, Nfat4, and Pparg genes were significantly elevated by treatment with nobiletin. From RNA sequence analysis, the T helper type 1 (Th1) and Th2 differentiation pathway was shown to be dominantly affected by nobiletin. Furthermore, molecular network analysis showed that GATA-3 is one of the candidate molecules for enhancement of IL-4 production. Treatment of splenocytes including antigen-presenting cells with nobiletin was sufficient for the induction of IL-4 production from DO11.10 mouse CD4⁺ T cells. Treatment of B cells and dendritic cells with nobiletin induced IL-4 production from CD4⁺ cells. Splenocytes from DO11.10 mice that had been treated with nobiletin produced more IL-4 than did splenocytes from control mice. These results revealed that the polymethoxylated flavonoid nobiletin specifically enhanced IL-4 production in vitro and in vivo.