title: TNF-alpha stimulation of MCP-1 expression is mediated by the Akt/PKB signal transduction pathway in vascular endothelial cells.
abstract: MCP-1 is expressed in a variety of cell types including vascular endothelial cells following induction by different stimuli such as tumor necrosis factor (TNF)-alpha. Although TNF-alpha stimulates MCP-1 expression and secretion, the mechanism by which TNF-alpha stimulates expression of the MCP-1 gene is not known. In this study, we examine the involvement of the phosphatidylinositol-3-OH kinase (PI3-kinase)-Akt/PKB pathway. Exposure of human umbilical vein endothelial cells (HUVECs) to TNF-alpha elicited the rapid phosphorylation of Akt/PKB. In HUVECs, wortmannin, a PI3-kinase inhibitor, inhibits TNF-alpha-mediated MCP-1 secretion at a dose-dependent manner. Constitutively active form of Akt/PKB induces transcription of the MCP-1 gene, and cotransfection of dominant negative Akt/PKB suppressed the activation of the MCP-1 promoter induced by TNF-alpha. These findings show that Akt/PKB participates in the TNF-alpha induction of MCP-1 gene transcription in endothelial cells.
authors.affiliation: First Department of Internal Medicine, Kagawa Medical University, 1750-1, Miki-Cho, Kita-Gun, Kagawa, 761-0793, Japan. mkoji@kms.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Murao
authors.forename: T
authors.initials: T
authors.lastname: Ohyama
authors.forename: H
authors.initials: H
authors.lastname: Imachi
authors.forename: T
authors.initials: T
authors.lastname: Ishida
authors.forename: W M
authors.initials: WM
authors.lastname: Cao
authors.forename: H
authors.initials: H
authors.lastname: Namihira
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: N C
authors.initials: NC
authors.lastname: Wong
authors.forename: J
authors.initials: J
authors.lastname: Takahara
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D018932:Chemokine CCL2; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin