Perifosine inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production via regulation multiple signaling pathways: new implication for Kawasaki disease (KD) treatment.

Abstract

Kawasaki disease (KD) is a multisystem vasculitis of unknown etiology, with coronary artery aneurysms occurring in majority of untreated cases. Tumor necrosis factor (TNF)-α is the pleiotropic inflammatory cytokine elevated during the acute phase of KD, which induces damage to vascular endothelial cells to cause systemic vasculitis. We here investigated the potential role of perifosine, a novel Akt inhibitor, on TNFα expression in LPS-stimulated macrophages and in ex-vivo cultured peripheral blood mononuclear cells (PBMCs) of acute KD patients. Here, we found that perifosine inhibited LPS-induced TNFα expression and production in mouse macrophages (RAW 264.7 cells and bone marrow-derived macrophages (BMDMs)). Meanwhile, perifosine administration down-regulated TNFα production in PBMCs isolated from acute KD patients. For the mechanism study, we found that perifosine significantly inhibited Akt and ERK/mitogen-activated protein kinases (MAPK) signaling, while activating AMP-activated protein kinase (AMPK) signaling in both patients' PBMCs and LPS-stimulated macrophages. Interestingly, although perifosine is generally known as an Akt inhibitor, our data suggested that ERK inhibition and AMPK activation, but not Akt inactivation were possibly involved in perifosine-mediated inhibition against TNFα production in monocytes. In conclusion, our data suggested that perifosine significantly inhibited TNFα production via regulation multiple signaling pathways. The results of this study should have significant translational relevance in managing this devastating disease.

• Authors: Jie Shen, Li Liang, Chunlin Wang
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 437 Issue 2 Pg. 250-5 (Jul 26 2013) ISSN: 1090-2104 [Electronic] United States
• PMID: 23806687 (Publication Type: Journal Article)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Lipopolysaccharides
• Tumor Necrosis Factor-alpha
• Phosphorylcholine
• perifosine
• Protein Kinases

Topics

• Animals
• Cell Line
• Enzyme Activation
• Lipopolysaccharides (toxicity)
• Macrophages (drug effects, enzymology, metabolism)
• Mice
• Mucocutaneous Lymph Node Syndrome (therapy)
• Phosphorylcholine (analogs & derivatives, pharmacology)
• Protein Kinases (metabolism)
• Signal Transduction
• Tumor Necrosis Factor-alpha (biosynthesis)