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

초록

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 E-2 (PGE(2)), interleukin-6 (IL-6), and interferon-gamma (INF-gamma) in a dose-dependent manner. Consistent with NO and PGE(2) 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-kappa B) activation through the inhibition of phosphorylation of I kappa B kinase (IKK), phosphorylation and degradation of I kappa B alpha, and nuclear translocation of NF-kappa B. In addition, MLB-C blocked LPS-induced serine 536 phosphorylation and transcriptional activity of RelA/p65 subunit of NF-kappa B. Further study demonstrated that MLB-C inhibited LPS-induced Akt phosphorylation, which is an upstream activator of NF-kappa B, 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-kappa B activation by inhibiting interconnected ROS/Akt/IKK/NF-kappa B signaling pathways. (C) 2012 Elsevier B.V. All rights reserved.

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