Abstract
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 microM LY29 or 100 nM WM. At these concentrations, LY29, but not WM, significantly inhibited constitutive and IL-1beta-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-kappaB (NF-kappaB). These results suggest that LY29 inhibits MCP-1 expression at least in part via suppression of NF-kappaB, independent of PI3K, and the structure of LY29 and LY30 may be a novel template for development of new anti-inflammatory drugs.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Chemokine CCL2 / analysis
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Chemokine CCL2 / antagonists & inhibitors*
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Chromones / pharmacology*
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Endothelium, Vascular / cytology
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Humans
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Interleukin-1 / pharmacology
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Morpholines / pharmacology*
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NF-kappa B / antagonists & inhibitors
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Phosphatidylinositol 3-Kinases*
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines / pharmacology
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Protein Serine-Threonine Kinases*
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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RNA, Messenger / analysis
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RNA, Messenger / drug effects
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Umbilical Veins / cytology
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Wortmannin
Substances
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Androstadienes
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Chemokine CCL2
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Chromones
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Interleukin-1
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Morpholines
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines
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Proto-Oncogene Proteins
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RNA, Messenger
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LY 303511
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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AKT1 protein, human
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Wortmannin