Secretory Phospholipases A2 Induce β-Glucuronidase Release and IL-6 Production from Human Lung Macrophages

Secretory phospholipases A 2 (sPLA 2 s) are a group of extracellular enzymes that release fatty acids at the sn -2 position of phospholipids. Group IIA sPLA 2 has been detected in inflammatory fluids, and its plasma level is increased in inflammatory diseases. To investigate a potential mechanism of sPLA 2 -induced inflammation we studied the effect of group IA (from cobra venom) and group IIA (human synovial) sPLA 2 s on human macrophages. Both sPLA 2 s induced a concentration- and Ca 2+ -dependent, noncytotoxic release of β-glucuronidase (16.2 ± 2.4% and 13.1 ± 1.5% of the total content with groups IA and IIA, respectively). Both sPLA 2 s also increased the rate of secretion of IL-6 and enhanced the expression of IL-6 mRNA. Preincubation of macrophages with inhibitors of the hydrolytic activity of sPLA 2 or cytosolic PLA 2 did not influence the release of β-glucuronidase. Incubation of macrophages with p -aminophenyl-mannopyranoside-BSA (mp-BSA), a ligand of the mannose receptor, also resulted in β-glucuronidase release. However, while preincubation of macrophages with mp-BSA had no effect on β-glucuronidase release induced by group IIA sPLA 2 , it enhanced that induced by group IA sPLA 2 . A blocking Ab anti-mannose receptor inhibited both mp-BSA- and group IIA-induced β-glucuronidase release. Taken together, these data indicate that group IA and IIA sPLA 2 s activate macrophages with a mechanism independent from their enzymatic activities and probably related to the activation of the mannose receptor or sPLA 2 -specific receptors. The secretion of enzymes and cytokines induced by sPLA 2 s from human macrophages may play an important role in inflammation and tissue damage associated with the release of sPLA 2 s.