Paeonol Inhibits Lipopolysaccharide-Induced HMGB1 Translocation from the Nucleus to the Cytoplasm in RAW264.7 Cells

Abstract

Transport of high-mobility group box 1 (HMGB1), a highly conserved non-histone DNA-binding protein, from the nucleus to the cytoplasm is induced by lipopolysaccharide (LPS). Secretion of HMGB1 appears to be a key lethal factor in sepsis, so it is considered to be a therapeutic target. Previous studies have suggested that paeonol (2'-hydroxy-4'-methoxyacetophenone), an active compound of Paeonia lactiflora Pallas, exerts anti-inflammatory effects. However, the effect of paeonol on HMGB1 is unknown. Here, we investigated the effect of paeonol on the expression, location, and secretion of HMGB1 in LPS-induced murine RAW264.7 cells. ELISA revealed HMGB1 supernatant concentrations of 615 ± 30 ng/mL in the LPS group and 600 ± 45, 560 ± 42, and 452 ± 38 ng/mL in cells treated with 0.2, 0.6, or 1 mM paeonol, respectively, suggesting that paeonol inhibits HMGB1 secretion induced by LPS. Immunohistochemistry and Western blotting revealed that paeonol decreased cytoplasmic HMGB1 and increased nuclear HMGB1. Chromatin immunoprecipitation microarrays suggested that HMGB1 relocation to the nucleus induced by paeonol might depress the action of Janus kinase/signal transducers and activators of transcription, chemokine, and mitogen-activated protein kinase pro-inflammatory signaling pathways. Paeonol was also found to inhibit tumor necrosis factor-α promoter activity in a dose-dependent manner. These results indicate that paeonol has the potential to be developed as a novel HMGB1-targeting therapeutic drug for the treatment of inflammatory diseases.

Paeonol attenuates inflammation by targeting HMGB1 through upregulating miR-339-5p

“…It has been confirmed that paeonol inhibits the production of proinflammatory cytokines (TNF-α and IL-1β) and affects the translocation and secretion of the late inflammatory factor HMGB1 42 . The nuclear protein HMGB1 is a late-stage lethal inflammatory factor that is translocated to the extracellular space as a signal for the spread of inflammation 16,43,44 .…”

Cynanchum paniculatum and Its Major Active Constituents for Inflammatory‐Related Diseases: A Review of Traditional Use, Multiple Pathway Modulations, and Clinical Applications

“…Paeonol suppresses inflammatory cytokines in LPS-induced macrophage cells and protects mice from lethal endotoxin shock by regulating the production of tumor necrosis factor- α (TNF- α ), IL-1 β , interleukin-6 (IL-6), and interleukin-10 (IL-10) via inactivation of I κ B α , ERK1/2, JNK, and p38 MAPK [ 27 , 36 ]. Furthermore, paeonol also reduces the nucleocytoplasmic transportation of extracellular high mobility group box 1 (HMGB1) by upregulating histone deacetylase 3 (HDAC3) [ 38 , 39 ]. It is worth noting that the anti-inflammatory and antioxidative activities of paeonol and its metabolites were found mostly through blocking MAPK/ERK/p38 signaling pathway and PI3K/Akt/NF- κ B pathway [ 27 , 40 , 41 ].…”

Reversal of Epithelial–Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids

“…Paeonol found in Paeonia suffruticosa (moutan cortex) can suppress LPS-induced HMGB1 translocation from the nucleus to the cytoplasm in RAW264.7 cells [235,236]. It (60-120 µM) can attenuate aging of MRC-5 cells and inhibit EMT of HaCaT cells induced by aging MRC-5 cell-conditioned medium [237].…”