Secretory phospholipases A2 induce beta-glucuronidase release and IL-6 production from human lung macrophages.
Secretory phospholipases A2 (sPLA2s) are a group of extracellular enzymes that release fatty acids at the sn-2 position of phospholipids. Group IIA sPLA2 has been detected in inflammatory fluids, and its plasma level is increased in inflammatory diseases. To investigate a potential mechanism of sPLA2-induced inflammation we studied the effect of group IA (from cobra venom) and group IIA (human synovial) sPLA2s on human macrophages. Both sPLA2s induced a concentration- and Ca2+-dependent, noncytotoxic release of beta-glucuronidase (16.2 +/- 2.4% and 13.1 +/- 1.5% of the total content with groups IA and IIA, respectively). Both sPLA2s 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 sPLA2 or cytosolic PLA2 did not influence the release of beta-glucuronidase. Incubation of macrophages with p-aminophenyl-mannopyranoside-BSA (mp-BSA), a ligand of the mannose receptor, also resulted in beta-glucuronidase release. However, while preincubation of macrophages with mp-BSA had no effect on beta-glucuronidase release induced by group IIA sPLA2, it enhanced that induced by group IA sPLA2. A blocking Ab anti-mannose receptor inhibited both mp-BSA- and group IIA-induced beta-glucuronidase release. Taken together, these data indicate that group IA and IIA sPLA2s activate macrophages with a mechanism independent from their enzymatic activities and probably related to the activation of the mannose receptor or sPLA2-specific receptors. The secretion of enzymes and cytokines induced by sPLA2s from human macrophages may play an important role in inflammation and tissue damage associated with the release of sPLA2s.
Triggiani
M
M
Division of Clinical Immunology and Allergy, University of Naples Federico II, Naples, Italy. triggian@unina.it
Granata
F
F
Oriente
A
A
De Marino
V
V
Gentile
M
M
Calabrese
C
C
Palumbo
C
C
Marone
G
G
D000814:Aniline Compounds / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007211:Indoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis*; D008168:Lung / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D008362:Mannosides / Q000494:pharmacology; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D054467:Phospholipases A2; D012710:Serum Albumin, Bovine / Q000494:pharmacology
D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D007211:Indoles; D015850:Interleukin-6; C095553:LY 311727; D008362:Mannosides; D012710:Serum Albumin, Bovine; C034056:4-aminophenylmannoside; D010741:Phospholipases A; D054467:Phospholipases A2; D005966:Glucuronidase