Neutral protease activation of peritoneal macrophage prostaglandin synthesis.

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Abstract
Treatment of murine macrophages with proteolytic enzymes can activate the synthesis and release of archidonic acid (ARA) metabolites. Murine peritoneal macrophage monolayers prelabeled with [14C]ARA were incubated with neutral proteases. Specific bacterial and mammalian proteases from various sources provoke the synthesis and release of prostaglandin [PG] E2 and other radiolabeled metabolites. Cells treated with the neutral proteases thrombin and trypsin did not release significant amounts of PGE2. Neutral protease treatment did not decrease cell viability (> 90%) and boiled protease preparations did not activate PG synthesis. Protease-activated PGE2 synthesis was inhibited by a variety of protease inhibitors [aprotinin, leupeptin and antipain] and synthetic substrates for neutral proteases. An inflammatory agent that induces macrophage neutral protease activity, 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulated synthesis and release of PGE2 in a dose- and time-dependent manner. TPA-activated PGE2 synthesis was also blocked by a variety of protease inhibitors. Apparently neutral proteases have the capacity to activate ARA metabolism and neutral proteases found in inflammatory reactions may influence PG production.