Type IIA secretory phospholipase A2 up-regulates cyclooxygenase-2 and amplifies cytokine-mediated prostaglandin production in human rheumatoid synoviocytes

Human type IIA secretory phospholipase A(2) (sPLA(2)-IIA) is induced in association with several immune-mediated inflammatory conditions. We have evaluated the effect of sPLA(2)-IIA on PC production in primary synovial fibroblasts from patients with rheumatoid arthritis (RA), At concentrations found in the synovial fluid of RA patients, exogenously added sPLA(2)-IIA dose-dependently amplified TNF-alpha -stimulated PGE(2) production by cultured synovial fibroblasts. Enhancement of TNF-alpha -stimulated PGE, production in synovial cells was accompanied by increased expression of cyclooxygenase (COX)-2 and cytosolic phospholipase A(2) (cPLA(2))-alpha. Blockade of COX-2 enzyme activity with the selective inhibitor NS-398 prevented both TNF-alpha -stimulated and sPLA(2)-IIA-amplified PGE(2) production without affecting COX-2 protein induction. However, both sPLA(2)-IIA-anlplificd PGE(2) production and enhanced COX-2 expression were blocked by the sPLA(2) inhibitor LY311727, Colocalization studies using triple-labeling immunofluorescence microscopy showed that sPLA(2)-IIA and cPLA(2)-alpha are coexpressed with COS-2 in discrete populations of CD14-positive synovial macrophages and synovial tissue fibroblasts from RA patients, Based on these findings, we propose a model whereby the enhanced expression of sPLA(2)-IIA by RA synovial cells up-regulates TNF-alpha -mediated PG production via superinduction of COX-2, Therefore, sPLA(2)-IIA may be a critical modulator of cytokine-mediated synovial inflammation in RA.