Mechanisms for the stimulation of prostanoid synthesis by cyclosporine and bacterial lipopolysaccharide.
Both cyclosporine and bacterial lipopolysaccharide enhance prostanoid synthesis and regulate the immune response. This study was designed to establish whether these agents affect prostanoid synthesis by common or different mechanisms. CsA and LPS stimulate prostanoid synthesis both in human monocytes and smooth muscle cells from guinea pig aorta. Only LPS stimulates synthesis in the presence of exogenous arachidonic acid. Dexamethasone totally blocks CsA but only partially inhibits LPS. CsA and LPS both enhance the release of labeled metabolites from cells labeled with arachidonic acid, but indomethacin only blocks the effect of LPS. CsA and the releasing agent calcium ionophore (A23187) both increase PGE2 and PGI2 synthesis without changing their relative concentrations, cause the release of free arachidonic acid, and lead to the formation of new metabolites that are not products of cyclooxygenase activity. Preincubation with either CsA or A23187 and a subsequent wash deplete the arachidonic acid pool available for prostanoid synthesis. Thus, A23187 and CsA have very similar effects on arachidonic acid metabolism. In contrast, LPS increases PGE2 and PGI2 synthesis and alters their relative concentrations, diminishes the relative concentration of free arachidonic acid, and enhances the formation of new metabolites that are products of cyclooxygenase activity. These differences are explained by mechanisms in which CsA promotes prostanoid synthesis through arachidonic acid release, and LPS promotes prostanoid synthesis through increased cyclooxygenase activity.
Zhang
H
H
Department of Physiological Chemistry, Ohio State University, Columbus 43210.
Kaseki
H
H
Davis
W B
WB
Whisler
R L
RL
Cornwell
D G
DG
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis*
D001095:Arachidonic Acids; D003524:Cyclosporins; D005227:Fatty Acids; D008070:Lipopolysaccharides; D011453:Prostaglandins; D016718:Arachidonic Acid; D000001:Calcimycin; D003907:Dexamethasone; D007213:Indomethacin