Anti-inflammatory activity of kurarinone involves induction of ho-1 via the keap1/nrf2 pathway

Abstract

Kurarinone, a flavonoid isolated from the roots of Sophora flavescens, was suggested to exert potent antioxidant and immunosuppressive effects. However, the underlying mechanisms remain unclear. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the antioxidant defense system with anti-inflammatory activity. In the present study, we demonstrated that kurarinone activated Nrf2 and increased the expression of antioxidant enzymes, including heme oxygenase-1 (HO-1). Mechanistically, kurarinone downregulated the expression of kelch-like ECH-associated protein 1 (KEAP1), subsequently leading to the activation of Nrf2. Kurarinone also inhibited the expression of the inflammatory cytokine, interleukin (IL)-1β, and inducible nitric oxide synthase (iNos) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. The overexpression of HO-1 suppressed the LPS-induced production of inflammatory mediators in RAW264.7 cells, and the immunosuppressive effects of kurarinone were partially inhibited by a treatment with Tin Protomorphyrin IX (TinPPIX), an inhibitor of HO-1. These results indicate that kurarinone activates the KEAP1/Nrf2 pathway to induce HO-1 expression, thereby exerting immunosuppressive effects.