Fumigaclavine C inhibits tumor necrosis factor α production via suppression of toll-like receptor 4 and nuclear factor κB activation in macrophages

Aims: Atherosclerosis is the main cause of cardiovascular disease and is widely treated with statins. However, there are a few cases of intolerable adverse reactions by statins; thus, there is still a need for new drugs to prevent atherosclerosis. The inflammation associated with the activation of Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF kappa B) has been shown to be an important factor in the development of atherosclerosis. In the current study, we investigated the anti-inflammatory action of the fungal alkaloid fumigaclavine C (FC), its effects on the TLR4 and NF kappa B signaling pathway, and its potential relevance as an anti-atherosclerotic agent. Main methods: The inhibitory effects of FC on tumor necrosis factor alpha (TNF alpha) production were determined by enzyme-linked immunosorbent assays (ELISA). The mRNA and protein expression of TLR4 and p65NF kappa B were detected by quantitative real-time polymerase chain reaction and western blot analysis, respectively. The effect of FC on NF kappa B was determined using the Dual-Luciferase reporter assay. Key findings: FC reduced TNF alpha production in LPS-stimulated human whole blood and RAW 264.7 macrophages via reduced I kappa B alpha phosphorylation associated with the decreased expression of p65NF kappa B. FC also suppressed LPS-induced TLR4 overexpression at the mRNA and protein level. Significance: FC attenuated TNF alpha via the TLR4-NF kappa B signaling transduction pathway, suggesting that this alkaloid might serve as a promising molecule for anti-inflammatory treatment of atherosclerosis. Crown Copyright (C) 2011 Published by Elsevier Inc. All rights reserved.