Macrophage formation of angiostatin during inflammation. A byproduct of the activation of plasminogen.

TitleMacrophage formation of angiostatin during inflammation. A byproduct of the activation of plasminogen.
Publication TypeJournal Article
Year of Publication1998
AuthorsFalcone DJ, Khan KM, Layne T, Fernandes L
JournalJ Biol Chem
Date Published1998 Nov 20
KeywordsAngiostatins, Animals, Cell Division, Cells, Cultured, Endothelium, Vascular, Enzyme Activation, Exudates and Transudates, Fibrinolysin, Inflammation, Kringles, Macrophages, Macrophages, Peritoneal, Membrane Proteins, Metalloendopeptidases, Mice, Peptide Fragments, Plasminogen, Thioglycolates

Angiostatin is a potent inhibitor of tumor angiogenesis and the growth of metastatic foci. Recent studies have indicated that neoplastic cells can generate angiostatin directly or in cooperation with tumor-associated macrophages. In studies reported here, we determined whether angiostatin is generated in mice under non-neoplastic settings. Utilizing murine RAW264.7 macrophages and thioglycollate-elicited peritoneal macrophages, we demonstrate that angiostatin-like fragments are generated as a byproduct of the proteolytic regulation of membrane-bound plasmin. Plasmin proteolysis and subsequent loss in membrane-bound plasmin activity requires active plasmin but was unaffected by inhibitors of metalloproteinases. Lysine binding fragments of plasmin, isolated from macrophage-conditioned media utilizing affinity chromatography, appeared as a major (48 kDa) and two minor bands (42 and 50 kDa) in SDS-polyacrylamide gel electrophoresis and were immunoreactive with anti-kringle 1-3 IgG. Each peptide begins with Lys77 and contains the entire sequence of angiostatin. The affinity isolated plasmin fragments inhibited bFGF-induced endothelial cell proliferation. Lavage fluid recovered from the peritoneal cavities of mice previously injected with thioglycollate contained angiostatin-like plasmin fragments similar to those generated in vitro. This is the first demonstration that angiostatin-like plasmin fragments are generated in a non-neoplastic inflammatory setting. Thus, in addition to regulating pericellular plasmin activity, proteolysis of plasmin generates inactive kringle-containing fragments expressing angiostatic properties.

Alternate JournalJ Biol Chem
PubMed ID9813061
Grant ListR01-HL40819 / HL / NHLBI NIH HHS / United States
T32-HL07423-18 / HL / NHLBI NIH HHS / United States
Related Faculty: 
Domenick J. Falcone, Ph.D.

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