Flavonoids derived from liquorice suppress murine macrophage activation by up-regulating heme oxygenase-1 independent of Nrf2 activation

Liquiritigenin (LQG), isoliquiritin (ILQ) and isoliquiritigenin (ILG) are flavonoids derived from liquorice and all possess a similar chemical structural backbone. In the current study, we found that ILQ and ILG had suppressive effects on lipopolysaccharide (LPS)-induced inflammatory responses in murine macrophage by suppressing the iNOS and COX-2 proteins and mRNA expression. A mechanistic study indicated that the effect was associated with an induction of antioxidant and detoxification enzymes, including UGT1A1, NQO1, and heme oxygenase-1 (HO-1) mRNA expression. The regulator of these enzymes, nuclear factor-erythroid 2-related factor 2 (Nrf2), which plays a critical role in LPS-induced inflammatory responses, could be activated by ILQ and ILG. Additionally, ILQ and ILG promoted Nrf2 signaling activation by inhibiting the Kelch-like ECH-associated protein 1 (Keap1) and increasing Nrf2 translocation, inducing the expression of these antioxidant enzymes. We further found that ILQ and ILG induced HO-1 expression independent of Nrf2 expression. With respect to the effect of these compounds on NF-κB signaling, ILG was found to markedly inhibit IκBα degradation and phosphorylation, while LQG and ILQ had no significant effects. These results indicate that there are correlations between the anti-inflammatory responses and the chemical structural properties of these flavonoids.