Platelet-activating factor stimulates arachidonic acid metabolism in rat liver cells (C-9 cell line) by a receptor-mediated mechanism.
Platelet activating factor (PAF) stimulated production of prostaglandin (PG) I2, PGE2, and PGF2 alpha by rat liver cells (the C-9 cell line); as little as 0.2 nM PAF was effective. Enantio-PAF was 1000-fold less effective. Lyso-PAF, at levels ranging from 0.1 to 1.0 microM, did not stimulate PGI2 production. The synthesis of PGI2 was essentially complete in 10 min. The stimulation by PAF of PGI2 production was inhibited by the PAF antagonists L-659,989, kadsurenone, L-652,731, and BN 52021; the values for 50% inhibition (IC50) were 0.02, 0.19, 0.21, and 0.73 microM, respectively. The antagonists L-659,989 and BN 52021 had no effect on the levels of 6-keto-PGF1 alpha stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA), palytoxin, melittin, the Ca2+ ionophore-A-23187, colchicine, transforming growth factor alpha, or exogenous arachidonic acid. The effect of PAF on arachidonic acid metabolism was inhibited by prior exposure of the cells to PAF. Prior treatment of the rat liver cells at 37 degrees with the TPA-type tumor promoters TPA, teleocidin, and aplysiatoxin, as well as with the second stage tumor promoter mezerein, all of which activate the Ca2+/phospholipid-dependent protein kinase (protein kinase C), resulted not only in homologous desensitization to the TPA-type tumor promoters and mezerein, but also in heterologous desensitization to PAF. Stimulation of PGI2 production by palytoxin, the Ca2+ ionophore A-23187, or exogenous arachidonic acid was not inhibited by such prior treatments with the TPA-type tumor promoters. Prior treatment of the cells at 37 degrees for 30 min with the non-TPA-type tumor promoters okadaic acid or palytoxin, both of which do not activate protein kinase C, did not result in heterologous desensitization to PAF.
Levine
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Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02254.
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D002460:Cell Line; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000502:physiology; D043562:Receptors, G-Protein-Coupled
D001095:Arachidonic Acids; D002273:Carcinogens; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D016718:Arachidonic Acid; D015121:6-Ketoprostaglandin F1 alpha