Inducible macrophage cytotoxins. II. Tumor lysis mechanism involving target cell-binding proteases.
Thioglycollate-elicited C57BL/6 peritoneal exudate macrophage monolayers (PEMM) stimulated with poly I . poly C or LPS released a macrophage cytotoxin (MCT) that rapidly bound to syngeneic (EL 4) or allogeneic (NS-1, YAC-1) tumor cells but did not bind to normal splenocytes. No binding to human (K562) tumor cells was observed. PEMM stimulated with poly I . poly C destroyed allogeneic tumor cells (NS-1) when separated by cell-impermeable Millipore filters in vitro; in contrast, PEMM not stimulated with poly I . poly C were incapable of lysing targets when separated by membranes. The reversible inhibitors N alpha-p-tosyl-L-arginine methyl ester and soybean trypsin inhibitor and the irreversible inhibitors N alpha-p-tosyl-L-lysine chloromethyl ketone and phenylmethylsulfonyl fluoride, of trypsin-like proteases, significantly or totally inhibited MCT cell-lytic activity for L-929 cells in vitro. Furthermore, modification of MCT-associated arginine residues by 1,2-cyclohexanedione completely blocked lytic activity. MCT was concluded to be an inducible nonspecific cell-lytic effector molecule elaborated by activated macrophages, which could bind to potential target cells, and was itself or was associated with a protease.
D000818:Animals; D002460:Cell Line; D003603:Cytotoxins / Q000096:biosynthesis* / Q000302:isolation & purification; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000201:enzymology / Q000276:immunology*; D010447:Peptide Hydrolases / Q000276:immunology* / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D011480:Protease Inhibitors; D011485:Protein Binding; D013154:Spleen / Q000276:immunology
D003603:Cytotoxins; D008070:Lipopolysaccharides; D011480:Protease Inhibitors; D010447:Peptide Hydrolases; D011070:Poly I-C