Identification and isolation of a phospholipase A2 activating protein in human rheumatoid arthritis synovial fluid: induction of eicosanoid synthesis and an inflammatory response in joints injected in vivo.
Eicosanoids are important mediators of the destructive arthropathy observed in rheumatoid arthritis. The rate-limiting step in the eicosanoid synthesis pathway is the availability of free arachidonic acid. The phospholipase enzymes release arachidonic acid from membrane phospholipids and thus play an important role in the regulation of eicosanoid production. We have previously demonstrated enhanced phospholipase A2 and C enzyme activities in cells from patients with rheumatoid arthritis and have also described a phospholipase A2 activating protein (PLAP) in mammalian cell lines. In an attempt to determine the biochemical basis of enhanced phospholipase A2 activity found in patients with inflammatory joint disease, we examined synovial fluid from patients with rheumatoid arthritis for PLAP. To determine whether PLAP was specific for rheumatoid disease, we assayed specimens from patients with other arthropathies. Histologic examination of rheumatoid joint tissue, with the use of immunohistochemical techniques, demonstrated high concentration of PLAP in monocytes, macrophages, chondrocytes, vascular smooth muscle, and endothelial cells. Human PLAP could be biochemically isolated from synovial fluid from patients with rheumatoid arthritis and was found to be similar to PLAP previously isolated from murine and bovine sources. To determine whether PLAP could directly mediate any aspect of inflammatory disease, purified PLAP was injected into rabbit knee joints. This resulted in an acute inflammatory arthritis with synovial cell proliferation and synovial fluid leukocytosis. Purified PLAP also induced eicosanoid formation both in vivo and in vitro. With enzyme-linked immunosorbent assays, we found more PLAP in synovial fluid specimens from patients with rheumatoid arthritis compared with samples from patients with other inflammatory arthropathies as well as osteoarthritis, a noninflammatory arthropathy. These data suggest that PLAP may be responsible, at least in part, for some aspects of the destructive inflammatory arthropathy that is observed in patients with rheumatoid arthritis.
Bomalaski
J S
JS
Veterans Administration Medical Center, Medical College of Pennsylvania, Philadelphia.
Fallon
M
M
Turner
R A
RA
Crooke
S T
ST
Meunier
P C
PC
Clark
M A
MA
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000209:etiology / Q000378:metabolism*; D015777:Eicosanoids / Q000096:biosynthesis*; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D010741:Phospholipases A / Q000032:analysis*; D054467:Phospholipases A2; D011506:Proteins / Q000302:isolation & purification*; D012867:Skin / Q000737:chemistry; D013582:Synovial Fluid / Q000737:chemistry*
D015777:Eicosanoids; D011506:Proteins; C055324:phospholipase A2-activating protein; D010741:Phospholipases A; D054467:Phospholipases A2