Malabaricone C suppresses lipopolysaccharide-induced inflammatory responses via inhibiting ROS-mediated Akt/IKK/NF-κB signaling in murine macrophages

Abstract

Malabaricone C (MLB-C), isolated from nutmeg, is a phenolic diarylnonanoid that is known to exert a variety of pharmacological activities. In the present study, we investigated the molecular actions of MLB-C against lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 cells and murine peritoneal macrophages. MLB-C inhibited the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-6 (IL-6), and interferon-γ (INF-γ) in a dose-dependent manner. Consistent with NO and PGE2 inhibition, MLB-C suppressed LPS-induced inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression as well as the promoter activities of COX-2 and iNOS. MLB-C pretreatment prevented LPS-induced nuclear factor-kappa B (NF-κB) activation through the inhibition of phosphorylation of IκB kinase (IKK), phosphorylation and degradation of IκBα, and nuclear translocation of NF-κB. In addition, MLB-C blocked LPS-induced serine 536 phosphorylation and transcriptional activity of RelA/p65 subunit of NF-κB. Further study demonstrated that MLB-C inhibited LPS-induced Akt phosphorylation, which is an upstream activator of NF-κB, by reducing reactive oxygen species (ROS) accumulation, without affecting phosphorylation of mitogen-activated protein kinases (MAPKs). These findings indicate that MLB-C exerts an anti-inflammatory effect through the inhibition of NF-κB activation by inhibiting interconnected ROS/Akt/IKK/NF-κB signaling pathways.