Both the kind and magnitude of stimulus are important in overcoming the negative regulation of macrophage activation by PGE2.
Macrophages activated for tumor cell killing by bacterial lipopolysaccharide (LPS) were shown to lose their cytolytic activity if exposed to physiological levels of prostaglandin E2 (PGE2). Increasing the LPS stimulus more than 100-fold over the amount needed to activate the cells did not substantially increase their resistance to the negative regulatory effect of PGE2. By contrast, killing mediated by macrophages activated by a mixture of LPS and gamma interferon was maintained. The degree of resistance conferred was directly related to the magnitude of the stimulus employed, reaching the point where not even 10(-5) M PGE2 would diminish killing. Killing by both activated resident and inflammatory peritoneal macrophages could be maintained, but it was easier to do so if the cells had been elicited by an inflammatory stimulus. A preparation of type I interferons produced by cells of the macrophage cell line J774A. 1 behaved similarly, but was over 500 times less efficient at helping to maintain killing than gamma (type II) interferon was. Alpha interferon alone, i.e., without LPS, was capable both of activating macrophages and of maintaining the activated state in the presence of PGE2. The capacity for both activation and maintenance could be strikingly enhanced, however, by mixing alpha and gamma interferons together under conditions that were free of detectable LPS. The data reported here collectively suggest that induction and maintenance of macrophage activation may be separable mechanistically, and that the interferons are important to host defense not only because they participate in the induction of macrophage activation for tumor cell killing but also because they help to maintain the activated state once it has been induced.
D000818:Animals; D015232:Dinoprostone; D007370:Interferon Type I / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010537:Peritoneum / Q000166:cytology; D011458:Prostaglandins E / Q000494:pharmacology*
D007370:Interferon Type I; D008070:Lipopolysaccharides; D011458:Prostaglandins E; D007371:Interferon-gamma; D015232:Dinoprostone