Malabaricone C suppresses lipopolysaccharide-induced inflammatory responses via inhibiting ROS-mediated Akt/IKK/NF-κB signaling in murine macrophages.
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-γ (INF-γ) 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-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.
Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon 200-701, Republic of Korea.
Jungwon
J
Kang
Nara
N
Tae
Byung Sun
BS
Min
Jongseon
J
Choe
Jeong-Hyung
JH
Lee
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology; D051550:I-kappa B Kinase / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D009569:Nitric Oxide / Q000276:immunology; D052247:Nitric Oxide Synthase Type II / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D012118:Resorcinols / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D012118:Resorcinols; D009569:Nitric Oxide; C071787:malabaricone C; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D015232:Dinoprostone