TNF-alpha stimulation of MCP-1 expression is mediated by the Akt/PKB signal transduction pathway in vascular endothelial cells.
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.
Murao
K
K
First Department of Internal Medicine, Kagawa Medical University, 1750-1, Miki-Cho, Kita-Gun, Kagawa, 761-0793, Japan. mkoji@kms.ac.jp
Ohyama
T
T
Imachi
H
H
Ishida
T
T
Cao
W M
WM
Namihira
H
H
Sato
M
M
Wong
N C
NC
Takahara
J
J
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
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