Alpha-Lipoic Acid Suppresses Extracellular Histone-Induced Release of the Inflammatory Mediator Tumor Necrosis Factor-α by Macrophages

Background/Aims: This study investigated signaling pathways via which extracellular histones induce the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) release from the macrophage cell line RAW 264.7 and the anti-inflammatory efficacy of the antioxidant alpha-lipoic acid (ALA). Methods: ELSA and western blotting analyses were conducted to detect the release of INF-alpha from histone-stimulated RAW 264.7 macrophages and the associated phospho-activation of MAPKs (ERK and p38) and NF-kappa B p65. The effects of ALA on the release of TNF-alpha and phospho-activation of the MAPKs and NF-kappa B p65 were studied. P < 0.05 was considered statistically significant. Results: Extracellular histones dose dependently induced TNF-alpha. release from RAW 264.7 cells and increased the phosphorylation of p38, ERK, and NF-kappa B p65. TNF-alpha, release was markedly suppressed by p38. ERK, and NF-kappa B inhibitors. ALA reduced histone-induced TNF-alpha, release, ERK/p38 MAPK activation, and NF-kappa B activation without affecting macrophage viability. Conclusion: Histones induce TNF-alpha. release from macrophages by activating the MARK and NF-kappa B signaling pathways, while ALA suppresses this response by inhibiting ERK, p38 and NF-kappa B. These findings identify potentially critical inflammatory signaling pathways in sepsis and molecular targets for sepsis treatment. (C) 2017 The Author(s) Published by S. Karger AG, Basel