LY294002 inhibits monocyte chemoattractant protein-1 expression through a phosphatidylinositol 3-kinase-independent mechanism

The effects of LY294002 (LY29) and wortmannin (WM), inhibitors of phosphatidylinositol 3-kinase (PI3K), on monocyte chemoattractant protein-1 (MCP-1) expression by human umbilical vein endothelial cells were investigated. Complete inhibition of interleukin (IL)-1beta-induced Akt phosphorylation occurred at 50 muM LY29 or 100 nM WM. At these concentrations, LY29, but not WM, significantly inhibited constitutive and IL-10-induced MCP-1 expression at both protein and mRNA levels. LY303511 (LY30), an inactive analogue of LY29, also inhibited MCP-1 expression. LY29 and LY30 inhibited activation of nuclear factor-kappabeta (NF-kappabeta). These results suggest that LY29 inhibits MCP-1 expression at least in part via suppression of NF-kappabeta, independent of PI3X, and the structure of LY29 and LY30 may be a novel template for development of new anti-inflammatory drugs. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.