Dihydropyrazine suppresses TLR4-dependent inflammatory responses by blocking MAPK signaling in human hepatoma HepG2 cells

• Published in: Journal of toxicological sciences Vol. 47; no. 9; pp. 381 - 387
• Main Authors: Sawai, Madoka, Miyauchi, Yuu, Ishida, Takumi, Takechi, Shinji
• Format: Journal Article
• Language: English
• Published: Suita The Japanese Society of Toxicology 2022; Japan Science and Technology Agency
• Subjects: Activator protein 1; Biocompatibility; Chemokines; Cyclooxygenase-2; Dihydropyrazine; Extracellular signal-regulated kinase; Glycation products; Glycosylation; Hepatoma; HepG2 cells; Inflammatory diseases; Inflammatory response; Interleukin 6; Interleukins; Kinases; Lipopolysaccharides; MAP kinase; MAPK pathway; NF-κB protein; Phosphorylation; Protein kinase; Proteins; Signal transduction; Signaling; TLR4; TLR4 protein; Toll-like receptors; Transcription factors
• ISSN: 0388-1350; 1880-3989
• DOI: 10.2131/jts.47.381

Dihydropyrazines (DHPs), including 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), are glycation products generated through non-enzymatic reactions in vivo and in food. They are recognized as compounds that are toxic to organisms as they produce radicals. However, our previous study indicated that DHP-3 suppressed Toll-like receptor 4 (TLR4) expression and decreased the phosphorylation of nuclear factor-κB (NF-κB) in lipopolysaccharide (LPS)-treated HepG2 cells. TLR4 signaling is involved in the onset of various inflammatory diseases, and NF-κB and mitogen-activated protein kinase (MAPK) play important roles in TLR4 signaling. Thus, we aimed to elucidate the effects of DHP-3 on MAPK signaling and in turn on the activated TLR4 signaling pathway. In LPS-stimulated HepG2 cells, DHP-3 reduced the phosphorylation of MAPK, extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, and p38. The expression of c-jun, a subunit of activator protein-1, was decreased by DHP-3 treatment. Furthermore, DHP-3-induced suppression of MAPK signaling resulted in a decrease in various inflammatory regulators, such as interleukin-6, CC-chemokine ligand 2, and cyclooxygenase-2. These results suggest that DHP-3 exerts an inhibitory effect on TLR4-dependent inflammatory response by suppressing MAPK signaling.