Abstract
BackgroundHwang-Heuk-San (HHS), a Korean traditional herbal formula comprising four medicinal herbs, has been used to treat patients with inflammation syndromes and digestive tract cancer for hundreds of years; however, its anti-inflammatory potential is poorly understood. The aim of the present study was to investigate the anti-inflammatory effects of HHS using a lipopolysaccharide (LPS)-activated RAW 264.7 macrophage model.MethodsThe inhibitory effects of HHS on LPS-induced nitric oxide (NO), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) production were examined using Griess reagent and enzyme-linked immunosorbent assay (ELISA) detection kits. The effects of HHS on the expression of inducible NO synthase (iNOS), IL-1β and TNF-α, their upstream signal proteins, including nuclear factor κB (NF-κB), mitogen-activated protein kinases (MAPKs), and activator protein (AP-1), were also investigated.ResultsA noncytotoxic concentration of HHS significantly reduced the production of NO, IL-1β and TNF-α in LPS-stimulated RAW 264.7 cells, which was correlated with reduced expression of iNOS, IL-1β and TNF-α at the mRNA and protein levels. HHS efficiently blocked the phosphorylation of MAPKs, especially that of extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) but not that of the p38 MAPK. The reduced production of inflammatory molecules by HHS was followed by decreased activity of NF-κB and AP-1.ConclusionsThese results suggest that HHS may offer therapeutic potential for treating inflammatory diseases accompanied by macrophage activation.
Highlights
Hwang-Heuk-San (HHS), a Korean traditional herbal formula comprising four medicinal herbs, has been used to treat patients with inflammation syndromes and digestive tract cancer for hundreds of years; its anti-inflammatory potential is poorly understood
HHS inhibited the release of nitric oxide (NO) and expression of inducible NO synthase (iNOS) in LPS-stimulated RAW 264.7 cells NO production is a widely used indicator of macrophage activation among many inflammatory mediators. iNOS expression generated in activated macrophages mediates the synthesis of NO, which is released into the culture medium [22, 23]
HHS did not affect the total forms of the three mitogen-activated protein kinases (MAPKs), either in the presence or absence of LPS. These results indicated that the anti-inflammatory effect of HHS was possibly mediated via the blockage of extracellular signal regulated kinase (ERK) and Jin NH2-terminal kinase (JNK) phosphorylation but that it was independent of the activation of p38 MAPK
Summary
Hwang-Heuk-San (HHS), a Korean traditional herbal formula comprising four medicinal herbs, has been used to treat patients with inflammation syndromes and digestive tract cancer for hundreds of years; its anti-inflammatory potential is poorly understood. LPS can bind to toll-like receptor 4 (TLR4), which is expressed on macrophages This complex activates various cellular signaling events, including mitogen-activated protein kinases (MAPKs), and subsequently induces the activation of various. NF-κB activation occurs via phosphorylation and subsequent activation of MAPKs, followed by degradation of IκB bound to NF-κB, resulting in the translocation of NF-κB from the cytoplasm to the nucleus to promote the expression of various proinflammatory genes [6, 11]. AP-1 is an important regulator of gene expression involved in inflammation activation, and it forms heterodimer complexes with c-Jun and c-Fos. Various factors, including growth factors, cytokines, and stress, induce AP-1 [7, 8]. Treatments aimed at inhibiting MAPKs and NF-κB, as well as AP-1, may have potential therapeutic advantages as anti-inflammatory agents [12, 13]
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