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ToolsGuha, Mausumee, O'Connell, Maria A., Pawlinski, Rafal, Hollis, Angela, McGovern, Patricia, Yan, Shi-Fang, Stern, David and Mackman, Nigel (2001) Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression. Blood, 98 (5). pp. 1429-1439. ISSN 0006-4971
Full text not available from this repository.Abstract
Lipopolysaccharide (LPS) induces human monocytes to express many proinflammatory mediators, including the procoagulant molecule tissue factor (TF) and the cytokine tumor necrosis factor alpha (TNIF-alpha). The TF and TNF-alpha genes are regulated by various transcription factors, including nuclear factor (NF)-kappaB/Rel proteins and Egr-1. In this study, the role of the MEK-ERK1/2 mitogen-activated protein kinase (MAPK) pathway in LIPS induction of TF and TNF-alpha gene expression in human monocytic cells was investigated. The MAPK kinase (MEK)1 inhibitor PD98059 reduced LPS induction of TF and TNIF-alpha expression in a dose-dependent manner. PD98059 did not affect LPS-induced nuclear translocation of NF-kappaB/Rel proteins and minimally affected LPS induction Of KB-dependent transcription. In contrast, PD98059 and dominant-negative mutants of the Ras-Raf1-MEK-ERK (extacellular signal-regulated kinase) pathway strongly inhibited LPS induction of Egr-1 expression. In kinetic experiments LPS induction of Egr-1 expression preceded induction of TF expression. In addition, mutation of the Egr-1 sites in the TF and TNF-alpha promoters reduced expression of these proinflammatory genes. It was demonstrated that LPS induction of the Egr-1 promoter was mediated by 3 SRE sites, which bound an LIPS-Inducible complex containing serum response factor and Elk-1. LPS stimulation transiently induced phosphorylation of Elk-1 and increased the functional activity of a GAL4-Elk-1TA chimeric protein via the MEK-ERK1/2 pathway. The data indicate that LPS induction of Egr-1 gene expression is required for maximal induction of the TNF-alpha and TF genes in human monocytic cells. (C) 2001 by The American Society of Hematology.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | activation,factor messenger-rna,transcriptional,factor gene-expression,binding proteins,serum response elements,ternary complex factors,c-jun,epithelial-cells,factor-kappa-b,bacterial lipopolysaccharide |
| Faculty \ School: | Faculty of Science > School of Pharmacy (former - to 2024) |
| UEA Research Groups: | Faculty of Science > Research Groups > Pharmaceutical Cell Biology (former - to 2017) Faculty of Science > Research Groups > Molecular and Tissue Pharmacology |
| Depositing User: | Rachel Smith |
| Date Deposited: | 06 Jun 2011 15:38 |
| Last Modified: | 28 Mar 2025 04:50 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/31777 |
| DOI: | 10.1182/blood.V98.5.1429 |
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