Kawasaki disease (KD) is a multisystem vasculitis of unknown etiology, with coronary artery aneurysms occurring in majority of untreated cases. Tumor necrosis factor (TNF)-alpha 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 TNF alpha 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 TNF alpha expression and production in mouse macrophages (RAW 264.7 cells and bone marrow-derived macrophages (BMDMs)). Meanwhile, perifosine administration down-regulated TNF alpha 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 TNF alpha production in monocytes. In conclusion, our data suggested that perifosine significantly inhibited TNF alpha production via regulation multiple signaling pathways. The results of this study should have significant translational relevance in managing this devastating disease. (C) 2013 Elsevier Inc. All rights reserved.