Molecular Mechanism of the Protective Effect of Zerumbone on Lipopolysaccharide-Induced Inflammation of THP-1 Cell-Derived Macrophages.

ABSTRACT

Unregulated inflammatory responses lead to massive production of macrophages-activating inflammatory cytokines and chemokines, which may induce diabetes, cancer, and atherosclerosis. Macrophages differentiated from human monocyte (THP-1) have been extensively used in in vitro inflammation models in recent studies. Zerumbone is a major component of the essential oil of Zingiber zerumbet Smith, a type of wild ginger. In this study, we investigated the effects of zerumbone on the secretion of pro-inflammatory cytokines and its underlying mechanistic regulation in lipopolysaccharide (LPS)-activated inflammation of THP-1 cell-derived macrophages. Nuclear factor (NF)-κB and toll-like receptors (TLRs) are known to play important roles in inflammation and immunity. If pathogens enter the host, TLRs recognize the pathogens and signal for the activation of NF-κB to induce inflammatory gene products, such as cytokines. We demonstrated that zerumbone inhibits the secretion of pro-inflammatory cytokines and the induction of NF-κB p65 in LPS-activated inflammation of THP-1 cell-derived macrophages. In addition, zerumbone significantly inhibited mRNA and protein levels of TLR-2/4, and the expression of myeloid differentiation factor 88 (MyD88) adaptor proteins in the LPS-activated inflammation of THP-1 cell-derived macrophages. Moreover, we showed that zerumbone (1-10 µM) regulated histone deacetylase (HDAC) activity and the expression of HDAC genes. H3K9ac, H3K27ac, and H3K4me2 are inducible histone marks that activate gene expression. Treatment with LPS upregulated H3K9ac, H3K27ac, and H3K4me2 in THP-1 cell-derived macrophages; however, this upregulation was decreased by zerumbone treatment. Therefore, these results provide evidence that zerumbone may have therapeutic benefits for chronic inflammatory diseases.