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

Abstract

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

Protection against neutrophil extracellular trap (NET) toxicity by antioxidant monoHER

“…27 Histones are reported to enhance the production of proinflammatory cytokine tumor necrosis factor-alfa (TNFα), resulting in an oxidative stress condition. 28,29 Both high expression of TNF-α and oxidative stress activate caspase-dependent cell death. 29 In our study, the toxic effect of histone 3 was counteracted by antioxidant monoHER.…”

“…28,29 Both high expression of TNF-α and oxidative stress activate caspase-dependent cell death. 29 In our study, the toxic effect of histone 3 was counteracted by antioxidant monoHER. This might also involve the ability of monoHER to efficiently scavenge ROS, thereby stopping oxidative stress signalinginduced cell death as showed in Figure 5.…”

The Beneficial Effects of Alpha Lipoic Acid Supplementation on Lp-PLA2 Mass and Its Distribution between HDL and apoB-Containing Lipoproteins in Type 2 Diabetic Patients: A Randomized, Double-Blind, Placebo-Controlled Trial

“…Therefore, the beneficial effects of ALA supplementation against Lp-PLA2 that are observed in our study might result from its reductive effects on ox-LDL serum levels. On the other hand, according to some in vitro studies, ALA attenuates P38 MAPK activation [58][59][60]. Then, we can consider the possibility that ALA indirectly downregulates Lp-PLA2 gene expression by suppressing the P38 MAPK activation.…”

Alpha Lipoic Acid: A Therapeutic Strategy that Tend to Limit the Action of Free Radicals in Transplantation

“…This anti-inflammatory activity is mediated by the inhibition of phosphorylation of IκBα and the translocation of NF-κB to the nucleus [ 28 ]. Moreover, a recent study shows, in a macrophage cell line, that ALA inhibits extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase 14 and NF-κB activation induced by extracellular histones [ 29 ]. Therefore, the beneficial effect of ALA, or its reduced form, DHLA, is mediated through different mechanisms of action depicted in Figure 1 .…”