Labdanolic acid methyl ester (LAME) exerts anti-inflammatory effects through inhibition of TAK-1 activation.

Abstract

Labdane derivatives obtained from the diterpenoid labdanediol suppressed NO and PGE(2) production in LPS-stimulated RAW 264.7 macrophages. However, mechanisms involved in these inhibitory effects are not elucidated. In this study, we investigated the signaling pathways involved in the anti-inflammatory effects of labdanolic acid methyl ester (LAME) in peritoneal macrophages and examined its therapeutic effect in a mouse endotoxic shock model. LAME reduced the production of NO and PGE(2) in LPS-activated macrophages. This effect involved the inhibition of NOS-2 and COX-2 gene expression, acting at the transcription level. Examination of the effects of the diterpene on NF-κB signaling showed that LAME inhibits the phosphorylation of IκBα and IκBβ, preventing their degradation and the nuclear translocation of the NF-κB p65 subunit. Moreover, inhibition of MAPK signaling was also observed. A further experiment revealed that LAME inhibited the phosphorylation of transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1), an upstream signaling molecule required for IKK and mitogen-activated protein kinases (MAPKs) activation. Inflammatory cytokines such as IL-6, TNF-α and IP-10 were downregulated in the presence of this compound after stimulation with LPS. Additionally, LAME also improved survival in a mouse model of endotoxemia and reduced the circulatory levels of cytokines (IL-6, TNF-α). In conclusion, these results indicate that labdane diterpene LAME significantly attenuates the pro-inflammatory response induced by LPS both in vivo and in vitro.

• Authors: Irene Cuadrado, Florencia Cidre, Sandra Herranz, Ana Estevez-Braun, Beatriz de las Heras, Sonsoles Hortelano
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 258 Issue 1 Pg. 109-17 (Jan 01 2012) ISSN: 1096-0333 [Electronic] United States
• PMID: 22036724 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Diterpenes
• Lipopolysaccharides
• NF-kappa B
• labdanolic acid methyl ester
• Nitric Oxide
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• Dinoprostone

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Dinoprostone (antagonists & inhibitors)
• Diterpenes (pharmacology)
• Lipopolysaccharides (pharmacology)
• MAP Kinase Kinase Kinases (antagonists & inhibitors)
• MAP Kinase Signaling System (drug effects)
• Macrophages (drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• NF-kappa B (antagonists & inhibitors)
• Nitric Oxide (antagonists & inhibitors)