Mechanisms of prostanoid synthesis in human synovial cells: cytokine-peptide synergism.
Bradykinin (BK)2 and interleukin-1 (IL-1) interact synergistically to stimulate prostaglandin synthesis in human synovial fibroblast-like cells. The effect of BK is rapid and correlates with its capacity to elevate cytosolic levels of calcium ([Ca2+]i), while IL-1's effect is slow and s dependent upon de novo protein synthesis. The mechanism of this synergistic interaction was investigated. In the basal state, high levels of arachidonic acid (AA) were spontaneously released from synovial cells but near absent levels of cyclooxygenase activity prevented metabolism of AA to prostanoid. BK was a potent stimulus for elevating AA, but not prostaglandins, above basal levels. IL-1, in contrast, increased prostaglandins but not AA, above basal levels. IL-1 treatment was not associated with a loss or redistribution of AA among phospholipid classes. These results are consistent with high basal phospholipase activity in synovial cells and demonstrate the ability of BK, presumably via its ability to raise [Ca2+]i, to further elevate this activity(ies). Metabolism of AA to prostanoid is minimal in resting and BK-stimulated synovial cells, however, without the concomitant induction of cyclooxygenase activity by IL-1. These studies clarify the different, but synergistic, mechanisms of action of a peptide and cytokine in stimulating prostanoid synthesis in synovial cells. In addition, these data extend the results of previous investigations in demonstrating that basal phospholipase activity provides sufficient AA substrate for IL-1 induced prostanoid synthesis without invoking the concomitant induction of phospholipase activity by IL-1.
Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
J M
JM
Bathon
F H
FH
Chilton
W C
WC
Hubbard
M C
MC
Towns
N J
NJ
Solan
D
D
Proud
D016718:Arachidonic Acid / Q000378:metabolism; D001920:Bradykinin / Q000008:administration & dosage*; D002478:Cells, Cultured; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000008:administration & dosage; D007375:Interleukin-1 / Q000008:administration & dosage*; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000378:metabolism; D050356:Lipid Metabolism; D010741:Phospholipases A / Q000235:genetics / Q000378:metabolism; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
D018836:Inflammation Mediators; D007375:Interleukin-1; D011453:Prostaglandins; D012333:RNA, Messenger; D016718:Arachidonic Acid; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D001920:Bradykinin