Development and production of novel inhibitory protein for inflammatory phospholipase A2

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(1) Extracellualr phospholipase A2 found in inflamed sites of human and rat was purified and characterized. Phospholipase A2 isolated from peritoneal exudates of rat treated with casein, that isolated from human synovial fluids in rheumatoid arthritis, that secreated from activated platelets of rat and rabbit share common structural and biochemical features. Possible roles, dynamics and regulation of these extracellular phospholipases in inflammatory processes have been studied.(2) The DNA clones coding for rat platelet phospholipase A2 (both cDNA and genomic DNA) were isolated and characterized. Rat haploid genome contained a single copy of gene that consisted of 5 exons. Judging from the deduced amino acid sequence, a typical single peptide sequence was located at the NH2 terminus of the mature enzyme, suggesting that the enzyme would function extracellularly.(3) We have purified two phospholipase A2 inhibitory proteins (37 and 33 KDa) from peritoneal fluid of dexamethasone-treated rats. The extracellular phospholipase A2 found in inflammatory sites differed from the exocrine phospholipase A2 in susceptibility to theses endogenous inhibitors; both proteins inhibited the activity of the extracellul ar phospholipase A2 purified from sites of inflammation but did not affect appreciably the activity of either porcine pancreatic or Naja naja venom phospholipas A2. The amino acid sequence of the NH2- terminal portion of the purified proteins did not resemble that of lipocortins so far reported, but it was almost identical to that of parts of human or mouse complement component C3. These findings may indicate that degraded products of C3 are involved in the regulation of activity of a class of mammalian phospholipase A2.