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Blood, 15 June 2007, Vol. 109, No. 12, pp. 5251-5259. Prepublished online as a Blood First Edition Paper on March 1, 2007; DOI 10.1182/blood-2006-10-051334. This Article Full Text (PDF) All Versions of this Article: blood-2006-10-051334v1 109/12/5251    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ahamed, J. Articles by Ruf, W. Search for Related Content PubMed PubMed Citation Articles by Ahamed, J. Articles by Ruf, W. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 12, 2006 Accepted February 27, 2007 Regulation of macrophage procoagulant responses by the tissue factor cytoplasmic domain in endotoxemia Jasimuddin Ahamed, Frank Niessen, Toru Kurokawa, Young Kyung Lee, Gourab Bhattacharjee, James H. Morrissey, and Wolfram Ruf* The Rockefeller University, New York, NY Dept of Immunology, The Scripps Research Institute, La Jolla, CA Dept of Biochemistry, University of Illinois, Champaign-Urbana, IL * Corresponding author; email: ruf{at}scripps.edu. Tissue factor (TF) is the primary initiator of coagulation and the TF pathway mediates signaling through protease-activated receptors (PARs). In sepsis, TF is upregulated as part of the pro-inflammatory response in lipopolysaccharide (LPS)-stimulated monocytes leading to systemic coagulation activation. Here we demonstrate that TF cytoplasmic domain-deleted (TFCT) mice show enhanced and prolonged systemic coagulation activation relative to wild-type upon LPS challenge. However, TFCT mice resolve inflammation earlier and are protected from lethality independent of changes in coagulation. Macrophages from LPS-challenged TFCT mice or LPS-stimulated, in vitro differentiated bone marrow-derived macrophages show increased TF mRNA and functional activity relative to wild-type, identifying upregulation of macrophage TF expression as a possible cause for the increase in coagulation of TFCT mice. Increased TF expression of TFCT macrophages does not require PAR2 and is specific for toll-like receptor, but not interferon receptor signaling. The presence of the TF cytoplasmic domain suppresses ERK1/2 phosphorylation that is reversed by p38 inhibition leading to enhanced TF expression specifically in wild-type, but not TFCT mice. The present study demonstrates a new role of the TF cytoplasmic domain in an autoregulatory pathway that controls LPS-induced TF expression in macrophages and procoagulant responses in endotoxemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Apostolopoulos, M. J. Hickey, L. Sharma, P. Davenport, L. Moussa, W. G. James, J. L. Gregory, A. R. Kitching, M. Li, and P. G. Tipping The cytoplasmic domain of tissue factor in macrophages augments cutaneous delayed-type hypersensitivity J. Leukoc. Biol., April 1, 2008; 83(4): 902 - 911. [Abstract] [Full Text] [PDF] H. H. Versteeg, F. Schaffner, M. Kerver, H. H. Petersen, J. Ahamed, B. Felding-Habermann, Y. Takada, B. M. Mueller, and W. Ruf Inhibition of tissue factor signaling suppresses tumor growth Blood, January 1, 2008; 111(1): 190 - 199. [Abstract] [Full Text] [PDF] R. Pawlinski, M. Tencati, C. R. Hampton, T. Shishido, T. A. Bullard, L. M. Casey, P. Andrade-Gordon, M. Kotzsch, D. Spring, T. Luther, et al. Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy Circulation, November 13, 2007; 116(20): 2298 - 2306. [Abstract] [Full Text] [PDF]

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