Type IIA secretory phospholipase A2 up-regulates cyclooxygenase-2 and amplifies cytokine-mediated prostaglandin production in human rheumatoid synoviocytes.
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-alpha-stimulated PGE2 production by cultured synovial fibroblasts. Enhancement of TNF-alpha-stimulated PGE2 production in synovial cells was accompanied by increased expression of cyclooxygenase (COX)-2 and cytosolic phospholipase A2 (cPLA2)-alpha. Blockade of COX-2 enzyme activity with the selective inhibitor NS-398 prevented both TNF-alpha-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-alpha 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-alpha-mediated PG production via superinduction of COX-2. Therefore, sPLA2-IIA may be a critical modulator of cytokine-mediated synovial inflammation in RA.
Bidgood
M J
MJ
Department of Medicine, University of New South Wales, and Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales, Australia.
Jamal
O S
OS
Cunningham
A M
AM
Brooks
P M
PM
Scott
K F
KF
D000276:Adjuvants, Immunologic / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D016207:Cytokines / Q000502:physiology*; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism; D054501:Group II Phospholipases A2; D006801:Humans; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism; D008565:Membrane Proteins; D010741:Phospholipases A / Q000502:physiology*; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D013583:Synovial Membrane / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000276:immunology*
D000276:Adjuvants, Immunologic; D016207:Cytokines; D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2; D015232:Dinoprostone