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*
Department of Medicine, University of New South Wales, and
Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, New South Wales, Australia
Human type IIA secretory phospholipase A2
(sPLA2-IIA) is induced in association with several
immune-mediated inflammatory conditions. We have evaluated the effect
of sPLA2-IIA on PG production in primary synovial
fibroblasts from patients with rheumatoid arthritis (RA). At
concentrations found in the synovial fluid of RA patients, exogenously
added sPLA2-IIA dose-dependently amplified
TNF-
-stimulated PGE2 production by cultured synovial
fibroblasts. Enhancement of TNF--stimulated PGE2
production in synovial cells was accompanied by increased expression of
cyclooxygenase (COX)-2 and cytosolic phospholipase A2
(cPLA2)-. Blockade of COX-2 enzyme activity with the
selective inhibitor NS-398 prevented both TNF--stimulated and
sPLA2-IIA-amplified PGE2 production without
affecting COX-2 protein induction. However, both
sPLA2-IIA-amplified PGE2 production and
enhanced COX-2 expression were blocked by the sPLA2
inhibitor LY311727. Colocalization studies using triple-labeling
immunofluorescence microscopy showed that sPLA2-IIA and
cPLA2- are coexpressed with COX-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 sPLA2-IIA by RA
synovial cells up-regulates TNF--mediated PG production via
superinduction of COX-2. Therefore, sPLA2-IIA may be a
critical modulator of cytokine-mediated synovial inflammation in
RA.
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