Interleukin‐1‐Induced Prostaglandin E2 Biosynthesis in Human Synovial Cells Involves the Activation of Cytosolic Phospholipase A2 and Cyclooxygenase‐2

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Abstract
Treatment of human synovial cells with interleukin‐1 (IL‐1) results in a large increase in the production of prostaglandin E, (PGE2), a function in which the activation of phospholipase A2 (PLA2) is a key step. In order to identify the enzymes that are linked to IL‐1‐mediated arachidonate availability and subsequent PGE2 production, we have investigated the changes in gene expression of the 85‐kDa cytosolic PLA2 (cPLA2), the 14‐kDa secretory PLA2 (sPLA2) and the two forms of cyclooxygenase in human synoviocytes after stimulation with recombinant IL‐1β. Northern‐blot analysis revealed that both cPLA2 and cyclooxygenase‐2 mRNA were progressively upregulated upon exposure to IL‐1 for 5 hours and the glucocorticoid, dexamethasone, blocked the increased expression of these two genes. In contrast, IL‐1‐induced sPLA2 gene expression determined in the same cell samples was weak and most often rapid, and dexamethasone further stimulated it. In addition, IL‐1 did not modify the levels of the constitutive cyclooxygenase‐1. The cPLA2 and cyclooxygenase‐2 enzymic activities are dependent upon de novo synthesis of mRNA and protein, since they were inhibited by actinomycin D and cycloheximide. Our data suggest that the IL‐1‐induced production of PGE2 in human synoviocytes can be attributed to the stimulation of both cPLA2 and cyclooxygenase‐2. These enzymes may represent appropriate targets for selective blockade of prostanoid production in the inflammed joints.

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