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Related Collections Signal Transduction Gene Expression Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 September 2001, Vol. 98, No. 5, pp. 1429-1439 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor  expression by inducing Elk-1 phosphorylation and Egr-1 expression Mausumee Guha, Maria A. O'Connell, Rafal Pawlinski, Angela Hollis, Patricia McGovern, Shi-Fang Yan, David Stern, and Nigel Mackman From the Departments of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, CA; the Departments of Surgery and Physiology and Cellular Physics, College of Physicians and Surgeons of Columbia University, New York, NY; and the Department of Neuroanatomy, Institute of Zoology of Jagiellonian University, Krakow, Poland. Lipopolysaccharide (LPS) induces human monocytes to express many proinflammatory mediators, including the procoagulant molecule tissue factor (TF) and the cytokine tumor necrosis factor alpha (TNF-). The TF and TNF- genes are regulated by various transcription factors, including nuclear factor (NF)-B/Rel proteins and Egr-1. In this study, the role of the MEK-ERK1/2 mitogen-activated protein kinase (MAPK) pathway in LPS induction of TF and TNF- gene expression in human monocytic cells was investigated. The MAPK kinase (MEK)1 inhibitor PD98059 reduced LPS induction of TF and TNF- expression in a dose-dependent manner. PD98059 did not affect LPS-induced nuclear translocation of NF-B/Rel proteins and minimally affected LPS induction of B-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- 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 LPS-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- and TF genes in human monocytic cells. © 2001 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Hoffmann, J. Ashouri, S. Wolter, A. Doerrie, O. Dittrich-Breiholz, H. Schneider, E. F. Wagner, J. Troppmair, N. 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