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Blood, 1 June 2006, Vol. 107, No. 11, pp. 4383-4390. Prepublished online as a Blood First Edition Paper on February 14, 2006; DOI 10.1182/blood-2005-07-2872. This Article Full Text (PDF) All Versions of this Article: 2005-07-2872v1 107/11/4383    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 Mitchell, J. W Articles by Miles, L. A Search for Related Content PubMed PubMed Citation Articles by Mitchell, J. W Articles by Miles, L. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 19, 2005 Accepted January 24, 2006 Plasminogen Inhibits TNF-induced Apoptosis in Monocytes Jennifer W Mitchell*, Nagyung Baik, Francis J Castellino, and Lindsey A Miles Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, La Jolla, CA, USA Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA * Corresponding author; email: jwmitch{at}scripps.edu. Monocytes are major mediators of inflammation and apoptosis provides a mechanism for regulating the inflammatory response by eliminating activated macrophages. Furthermore, as a consequence of apoptosis, plasminogen binding is markedly increased on monocytoid cells. Therefore, we investigated the ability of plasminogen to modulate monocyte apoptosis. Apoptosis of monocytoid cells (human monocytes and U937 cells) was induced with either TNF or cycloheximide. When apoptosis was induced in the presence of increasing concentrations of plasminogen, apoptosis was inhibited in a dose-dependent manner with full inhibition achieved at 2 µM plasminogen. Plasminogen treatment also markedly reduced internucleosomal DNA fragmentation and reduced levels of active caspase 3, caspase 8 and caspase 9 induced by TNF or by cycloheximide. We examined the requirement for plasmin proteolytic activity in the cytoprotective function of plasminogen. A plasminogen active site mutant, [D(646)E]-Plg, failed to recapitulate the cytoprotective effect of wild-type plasminogen. Furthermore, antibodies against PAR1 blocked the anti-apoptotic effects of plasminogen. Our results suggest that plasminogen inhibits monocyte apoptosis. The cytoprotective effect of plasminogen requires plasmin proteolytic activity and requires PAR1. Because apoptosis of monocytes plays a key role in inflammation and atherosclerosis, these results provide insight into a novel role of plasminogen in these processes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Wu, L. Peng, G. A. McMahon, D. A. Lawrence, and W. P. Fay Recombinant Plasminogen Activator Inhibitor-1 Inhibits Intimal Hyperplasia Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1565 - 1570. [Abstract] [Full Text] [PDF] E. Pluskota, D. A. Soloviev, D. Szpak, C. Weber, and E. F. Plow Neutrophil Apoptosis: Selective Regulation by Different Ligands of Integrin {alpha}M{beta}2 J. Immunol., September 1, 2008; 181(5): 3609 - 3619. [Abstract] [Full Text] [PDF] V. Shpacovitch, M. Feld, M. D. Hollenberg, T. A. Luger, and M. Steinhoff Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity J. Leukoc. Biol., June 1, 2008; 83(6): 1309 - 1322. [Abstract] [Full Text] [PDF] A. A. Eddy and A. B. Fogo Plasminogen Activator Inhibitor-1 in Chronic Kidney Disease: Evidence and Mechanisms of Action J. Am. Soc. Nephrol., November 1, 2006; 17(11): 2999 - 3012. [Full Text] [PDF]

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