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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.
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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Plasminogen inhibits TNF -induced apoptosis in monocytes
Jennifer W. Mitchell,
Nagyung Baik,
Francis J. Castellino, and
Lindsey A. Miles
From the Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, La Jolla, CA; and the Department of Chemistry and Biochemistry, University of Notre Dame, IN.
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 antiapoptotic effect 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.
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