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.

Kurarinone Attenuates Collagen-Induced Arthritis in Mice by Inhibiting Th1/Th17 Cell Responses and Oxidative Stress

“…It induces antioxidant enzymes that inactivate reactive oxygen species, like heme oxygenase-1 (HO-1), GPX, and CAT. Kurarinone is known to activate the KEAP1/Nrf2/HO-1 pathway to exert immunomodulatory effects [ 18 ]. Therefore, we further studied kurarinone’s effects on expressions of Nrf2 and KEAP1 in the paw tissues of mice.…”

“…Kurarinone also attenuates levels of inducible nitric oxide synthase-dependent NO, interleukin (IL)-1β. It also activates extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK), p38 MAP kinases, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages [ 18 , 27 ]. Key inflammatory cytokines (e.g., IFN-γ, IL-1α, IL-1β, IL-4, IL-6, IL-17A, IL-22, and TNF-α) and chemokines (e.g., CCL17, CCL20, CCL27, and CXCL1) are reduced by kurarinone in mice with autoimmune encephalomyelitis (EAE).…”

“…In terms of cytoprotection, KEAP1-Nrf2 pathway is the major regulatory mechanism of endogenous and exogenous oxidative stress [ 17 ]. To be noted, the treatment of prostate cancer PC3 cells with kuraninone downregulates the expression of KEAP1 and subsequently activates Nrf2, which increases the expression of heme oxygenase-1 (HO-1), an antioxidant enzyme [ 18 ]. However, this effect is not found in mouse hippocampal HT22 cells treated with kuraninone [ 30 ].…”

“…Kurarinone also inhibits the progression of murine autoimmune encephalomyelitis (EAE) by inhibiting Th1 and Th17 cell differentiation and proliferation [ 15 ]. Moreover, it activates the KEAP1/Nrf2 pathway, a major regulator of oxidative stress [ 17 ], and it overexpresses antioxidant enzymes, like heme oxygenase-1 (HO-1), thereby exerting immunosuppression on the lipopolysaccharide (LPS)-induced production of inflammatory mediators in RAW264.7 macrophages [ 18 ]. Based on these findings, we hypothesized that kurarinone has a therapeutic effect on RA through regulating Th1/Th17 cell balance and antioxidative activity.…”

Distinct Effects of Escherichia coli,Pseudomonas aeruginosa and Staphylococcus aureus Cell Wall Component-Induced Inflammation on the Iron Metabolism of THP-1 Cells

“…HO-1 provides an anti-inflammatory effect as well, and it is activated by the NRF2 transcription factor, and regulated by inflammatory processes [ 70 ]. HO-1 releases CO by the degradation of heme, which attenuates inflammation [ 71 ].…”