IL-1 and related cytokines enhance thrombin-stimulated PGI2 production in cultured endothelial cells without affecting thrombin-stimulated von Willebrand factor secretion or platelet-activating factor biosynthesis.
We examined the effects of various cytokines on alpha-thrombin-stimulated prostaglandin (PG) I2 production, von Willebrand factor (vWF) secretion, and platelet-activating factor (PAF) synthesis in cultured human umbilical vein endothelial cells (HUVEC). A 24-h pretreatment with IL-1 beta doubled the low level of constitutive PGI2 production. In contrast, alpha-thrombin increased PGI2 production fivefold in untreated HUVEC. The most striking increase in PGI2 production was observed in IL-1 beta-treated HUVEC that were subsequently stimulated with thrombin. PGI2 production was two to three times greater than in untreated, thrombin-stimulated HUVEC and nearly eightfold greater than in IL-1 beta-treated but unstimulated HUVEC. Enhanced thrombin-stimulated PGI2 production was also observed in HUVEC pretreated with the related cytokines IL-1 alpha, TNF, or lymphotoxin. This cytokine effect was selective for PGI2 production because none of these cytokines altered either constitutive or thrombin-stimulated vWF secretion or PAF biosynthesis. IL-1 beta enhancement of thrombin-stimulated PGI2 production was concentration and time dependent and required protein synthesis. IL-1 beta pretreatment also enhanced PGI2 production in response to another agonist, histamine, and to exogenously added substrates, arachidonic acid or PGH2. Our results indicate that activation by IL-1 and related cytokines selectively primes endothelial cells for enhanced PGI2 production, but not vWF secretion or PAF synthesis, in response to thrombin and histamine. The evidence suggests that this effect is mediated through specific induction of biosynthetic enzymes for PGI2.
Zavoico
G B
GB
Division of Hematology, Brigham and Women's Hospital, Boston, MA 02115.
Ewenstein
B M
BM
Schafer
A I
AI
Pober
J S
JS
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002478:Cells, Cultured; D002855:Chromatography, Thin Layer; D003513:Cycloheximide / Q000494:pharmacology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D006632:Histamine; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000378:metabolism; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000378:metabolism; D013917:Thrombin; D014841:von Willebrand Factor / Q000502:physiology*
D001095:Arachidonic Acids; D007375:Interleukin-1; D010972:Platelet Activating Factor; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D014841:von Willebrand Factor; D016718:Arachidonic Acid; D044262:Prostaglandin H2; D006632:Histamine; D003513:Cycloheximide; D011464:Epoprostenol; D013917:Thrombin