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Related Collections Hemostasis, Thrombosis, and Vascular Biology Signal Transduction Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 January 2001, Vol. 97, No. 1, pp. 46-55 CHEMOKINES Multiple signaling pathways regulate NF-B-dependent transcription of the monocyte chemoattractant protein-1 gene in primary endothelial cells Matthias Goebeler, Reinhard Gillitzer, Karin Kilian, Kathrin Utzel, Eva-Bettina Bröcker, Ulf R. Rapp, and Stephan Ludwig From the Klinik und Poliklinik für Hautkrankheiten and the Institut für Medizinische Strahlenkunde und Zellforschung, University of Würzburg, Würzburg, Germany. The cytokine-induced C-C chemokine monocyte chemoattractant protein-1 (MCP-1) is an important regulator of leukocyte recruitment to sites of inflammatory challenge. Here, it is demonstrated that the widely distributed contact hapten NiCl2, like tumor necrosis factor  (TNF), induces monocyte-chemoattractant activity in primary human endothelial cells via induction of MCP-1. NiCl2 rapidly activated mitogen-activated protein (MAP) kinase p38, and inhibition of p38 partially blocked NiCl2-induced MCP-1 messenger RNA and protein expression. Both NiCl2- and TNF-induced MCP-1 synthesis was sensitive to D609, an inhibitor of phosphatidylcholine-dependent phospholipase C (PC-PLC). NiCl2-induced MCP-1 synthesis required activation of NF-B since mutation of NF-B-binding sites in the promoter resulted in complete loss of inducible promoter activity. Consistent with that finding, stimulation with NiCl2 or TNF activated IB kinase- (IKK), and transient transfection of dominant-negative IKK strongly inhibited NiCl2- and TNF-induced MCP-1 expression. However, D609 and the specific p38 inhibitor SB202190 did not affect NiCl2- and TNF-induced IKK activation, NF-B DNA-binding activity, or transcriptional activity of a Gal4p65 fusion protein. This indicates that p38- and PC-PLC-dependent pathways directly regulate the transcriptional activity of NF-B factors in the transcriptional complex. Consistent with that, inhibition of p38 blocked enhanced transcriptional activity induced by the transcriptional coactivator p300. Thus, it was concluded that at least 3 independent pathways regulate MCP-1 expression in endothelial cells. Its induction requires activation of the IKK/IB/NF-B signaling pathway, resulting in nuclear accumulation of p65 and subsequent recruitment of cofactors. Proper assembly and activity of this transcriptional complex is further modulated by the p38 MAP kinase cascade and a PC-PLC-dependent pathway. © 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: D. Spiering, M. Schmolke, N. Ohnesorge, M. Schmidt, M. Goebeler, J. Wegener, V. Wixler, and S. Ludwig MEK5/ERK5 Signaling Modulates Endothelial Cell Migration and Focal Contact Turnover J. Biol. Chem., September 11, 2009; 284(37): 24972 - 24980. [Abstract] [Full Text] [PDF] M. Del Corno, A. Michienzi, A. Masotti, L. Da Sacco, G. F. Bottazzo, F. Belardelli, and S. Gessani CC chemokine ligand 2 down-modulation by selected Toll-like receptor agonist combinations contributes to T helper 1 polarization in human dendritic cells Blood, July 23, 2009; 114(4): 796 - 806. [Abstract] [Full Text] [PDF] T. Aoki, H. Kataoka, R. Ishibashi, K. Nozaki, K. Egashira, and N. 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