Bradykinin is a potent and relatively selective stimulus for cytosolic calcium elevation in human synovial cells.
Previously, we have shown that bradykinin elicits the production of prostaglandin E2 (PGE2) in human synovial cells only after pre-exposure of the cells to IL-1. The observation that calcium ionophores, but not a variety of physiologic receptor-mediated agonists, can mimic bradykinin in its synergy with IL-1 led us to hypothesize that the ability of bradykinin to induce prostanoid synthesis was a result of its selective ability (among physiologic agonists) to raise the cytosolic free ionized calcium concentration ([Ca2+]i) levels of synovial cells. Extending this hypothesis, it follows that the relative potency of an agonist in inducing PGE2 production from IL-1-treated cells should be dependent on its ability to raise [Ca2+]i. In these studies, we have confirmed the potent ability of bradykinin to elevate [Ca2+]i in resting human synovial cells. That the effect of bradykinin on [Ca2+]i was mediated through the previously described synovial cell kinin receptor was confirmed by a pharmacologic profile consistent with a high affinity B2 kinin receptor. Furthermore, the relative specificity and potency of the PGE2 response of bradykinin in IL-1-treated cells was paralleled, in resting cells, by a similar pattern in the [Ca2+]i response. Finally, IL-1 had no direct effect on [Ca2+]i levels, nor did it alter agonist-induced elevations in [Ca2+]i. We conclude that the potency of a receptor-mediated agonist in inducing prostanoid synthesis in synovial cells is dependent on its ability to raise [Ca2+]i. However, this effect is not enough, in and of itself, to induce prostanoid synthesis; the concomitant induction by IL-1 of a PG-generating enzyme is also required.
Bathon
J M
JM
Johns Hopkins University School of Medicine, Department of Medicine, Baltimore, MD 21224.
Croghan
J C
JC
MacGlashan
D W
DW
Proud
D
D
D001920:Bradykinin / Q000502:physiology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D011458:Prostaglandins E / Q000096:biosynthesis*; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism*
D007375:Interleukin-1; D011458:Prostaglandins E; D001920:Bradykinin; D002118:Calcium