Prostaglandins enhance epidermal growth factor-induced DNA synthesis in hepatocytes by stimulation of E prostanoid 3 and F prostanoid receptors.
Prostaglandins stimulate hepatocyte proliferation in vivo and in vitro. We have examined the role of E prostanoid (EP) and F prostanoid receptors (FP) in enhancing the growth-stimulatory effect of epidermal growth factor (EGF) in cultured hepatocytes. The EP2 receptor agonist butaprost had no significant effect on EGF-induced DNA synthesis. EP1 receptor-selective antagonists did not affect the enhancement by prostaglandin E(2) of EGF-stimulated DNA synthesis. Sulprostone, misoprostol, and fluprostenol strongly enhanced DNA synthesis and inhibited glucagon-stimulated cAMP accumulation, indicating that they all activated EP3 receptors. Sulprostone and fluprostenol, and to a lesser extent misoprostol, stimulated accumulation of inositol phosphates. The effects of fluprostenol and sulprostone on phospholipase C (PLC) were inhibited by the FP receptor antagonist AL-8810 [9 alpha, 15R-dihydroxy-11 beta-fluoro-15-(2,3-dihydro-1H-inden-2-yl)-16,17,18,19,20-pentanor-prosta-5Z, 13E-dien-1-oic acid], indicating that this effect was mediated by FP receptors. Inhibition of protein kinase C with GF109203X [2-[1-(3-dimetylaminopropyl)-1H-indol-3-yl]-maleimide] resulted in a partial reduction of the growth stimulation induced by fluprostenol, indicating a minor role of FP receptors. Combining fluprostenol with misoprostol, but not with sulprostone, resulted in partially additive effects on DNA synthesis, suggesting that both EP3 and FP receptors are involved. Combining sulprostone with misoprostol did not result in additive effects on DNA synthesis, suggesting that EP4 receptors were not involved. We conclude that, although a minor effect is exerted by FP receptors, the growth-stimulatory effects of prostaglandins in rat hepatocytes are mediated mainly by EP3 receptors. We have found no evidence of EP1 receptor involvement.
Meisdalen
Kristin
K
Department of Pharmacology, Faculty of Medicine, University of Oslo, P.O. Box 1057 Blindern, N-0316 Oslo, Norway. k.b.meisdalen@medisin.uio.no
Dajani
Olav F
OF
Christoffersen
Thoralf
T
Sandnes
Dagny
D
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis*; D004815:Epidermal Growth Factor / Q000502:physiology*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D011453:Prostaglandins / Q000502:physiology*; D051381:Rats; D011982:Receptors, Prostaglandin / Q000819:agonists*; D018078:Receptors, Prostaglandin E / Q000819:agonists*; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype
D011453:Prostaglandins; C545637:Ptger1 protein, rat; C545646:Ptger2 protein, rat; C545649:Ptger3 protein, rat; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; C034671:prostaglandin F2alpha receptor; D004815:Epidermal Growth Factor; D004247:DNA