Macrophage-mediated tumor cell killing: regulation of expression of cytolytic activity by prostaglandin E.
The expression of nonspecific macrophage-mediated tumoricidal activity in vitro is a transient phenomenon. The work reported here shows that the loss of tumoricidal activity by mouse macrophages is attributable, at least in part, to the effects of prostaglandin E (PGE). The amount of PGE needed to inhibit the expression of cytolytic activity (2 x 10(-9) M) was readily synthesized and secreted by the same population of resident peritoneal macrophages that had been induced to kill tumor cells by exposure to 100 ng/ml bacterial lipopolysaccharide (LPS). Inhibitory concentrations of PGE were present in supernatants within the 1st hr after macrophages were exposed to LPS. In spite of this fact, cytolytic activity still developed, and 12 to 16 hr were required for the PGE to have its full inhibitory effect. Thus, PGE did not act by blocking the development of cytolytic activity. Treatment of LPS-stimulated macrophages with 10(-6) M indomethacin (or other cyclooxygenase inhibitors) prevented both PGE synthesis and the shut-off of cytolytic activity. The latter effect could be reversed by adding PGE2 to the cultures at a concentration of 10(-8) M. Lastly, PGE inhibited cytolytic activity mediated by indomethacin-treated macrophages only when activator was present: pulsing with PGE before the addition of LPS had a negligible inhibitory effect. These findings may help explain why intratumoral macrophages often lack nonspecific cytolytic capabilities.
D000818:Animals; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D011458:Prostaglandins E / Q000096:biosynthesis / Q000494:pharmacology*; D013997:Time Factors
D008070:Lipopolysaccharides; D011458:Prostaglandins E; D007213:Indomethacin