Abstract
The antioxidant and anti-inflammatory responses of (−)-methyl-oleocanthal (met-OLE), a new metabolite of the extra virgin olive oil (EVOO) phenolic oleocanthal (OLE), were explored in lipopolysaccharide (LPS)-induced murine peritoneal macrophages. Possible signaling pathways and epigenetic modulation of histones were studied. Met-OLE inhibited LPS-induced intracellular reactive oxygen species (ROS) and nitrite (NO) production and decreased the overexpression of the pro-inflammatory enzymes COX-2, mPGES-1 and iNOS in murine macrophages. In addition, met-OLE was able to significantly decrease the activation of p38, JNK, and ERK mitogen-activated protein kinases (MAPKs) and blocked canonical and non-canonical inflammasome signaling pathways. On the contrary, met-OLE upregulated haem oxigenase 1 (HO-1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) expression in treated cells. Finally, met-OLE pretreated spleen cells counteracted LPS induction, preventing H3K18 acetylation or H3K9 and H3K27 demethylation. Overall, these results provide novel mechanistic insights into the beneficial effects of met-OLE regarding the regulation of the immune–inflammatory response through epigenetic changes in histone markers. This revealing evidence suggests that the methylated metabolite of OLE may contribute significantly to the beneficial effects that are associated with the secoiridoid-related compound and the usual consumption of EVOO.
Highlights
Introduction published maps and institutional affilMacrophages are major components of the innate immune system and play a critical role in modulating inflammatory and immune responses [1]
LPS-stimulated macrophages disrupt the balance of the intracellular reduction–oxidation state, leading to oxidative stress, usually accompanied by damage that is mediated by reactive oxygen species (ROS) [3]
To identify whether the OLE derivative evoked an antioxidant effect on cells, we studied the nuclear factor (erythroid-derived 2)-like 2 (Nrf-2)/haem oxigenase 1 (HO-1) axis, measuring both protein expressions by immunoblotting
Summary
Macrophages are major components of the innate immune system and play a critical role in modulating inflammatory and immune responses [1]. Extracellular bacterial lipopolysaccharide (LPS) acts as pathogen-associated molecular pattern and is recognized by the Toll-like receptor (TLR)-4, inducing macrophages to an activated state, producing proinflammatory cytokines and chemokines and enhancing the expression of inflammatoryrelated enzymes, such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase (mPGES)-1, which synthesize nitric oxide (NO). LPS-stimulated macrophages disrupt the balance of the intracellular reduction–oxidation state, leading to oxidative stress, usually accompanied by damage that is mediated by reactive oxygen species (ROS) [3]. The process of gene expression of these pro-inflammatory mediators involves multiple signal transduction pathways, which are mainly through mitogen-activated protein kinases iations.
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