RRC ID 38689
Author Matsunaga T, Gohda E, Takebe T, Wu YL, Iwao M, Kataoka H, Yamamoto I.
Title Expression of hepatocyte growth factor is up-regulated through activation of a cAMP-mediated pathway.
Journal Exp. Cell Res.
Abstract Hepatocyte growth factor (HGF) is a multifunctional cytokine with mitogenic, motogenic, morphogenic, and tumor-suppressing activities. Despite the broad spectrum of its biological activities, HGF is most likely the physiological hepatotrophic factor that triggers or modulates liver regeneration. Regulatory mechanisms for HGF production are crucial for understanding the control of liver regeneration. We previously reported that HGF production by human skin fibroblasts is stimulated by a protein kinase C (PKC)-mediated pathway. We determined here whether gene expression and production of HGF in human skin fibroblasts can be induced via activation of a cAMP-mediated pathway. HGF secretion by the cells was markedly stimulated by the cAMP-elevating agents, forskolin, cholera toxin, prostaglandin E2 (PGE2), and 3-isobutyl-1-methylxanthine, as well as by the membrane-permeable cAMP analogues, 8-bromo-cAMP and dibutyryl cAMP. The dose-response curves of induction of HGF secretion by cholera toxin and forskolin were nearly parallel with those of the intracellular cAMP levels. HGF mRNA levels did not significantly increase at 5 and 10 h, but increased considerably 15 h or more after the addition of cholera toxin. Forskolin, 8-bromo-cAMP, and PGE2 also caused appreciable up-regulation of HGF gene expression with a similar time course. Although human skin fibroblasts of various origins secreted variable amounts of HGF, the cAMP-elevating agents and the cAMP analogues caused a very marked increase in HGF production in all of them. The agents also enhanced highly active HGF secretion by MRC-5 human embryonic lung fibroblasts. Dexamethasone and transforming growth factor-beta 1, which inhibit PKC-mediated HGF secretion, down-regulated HGF mRNA expression and HGF production in the cells treated with the cAMP-elevating agents and the cAMP analogues. These results indicate that HGF expression in human skin fibroblasts is stimulated by activation of a cAMP-mediated pathway.
Volume 210(2)
Pages 326-35
Published 1994-2
DOI 10.1006/excr.1994.1045
PII S0014-4827(84)71045-7
PMID 7507855
MeSH 1-Methyl-3-isobutylxanthine / pharmacology 8-Bromo Cyclic Adenosine Monophosphate / pharmacology Bucladesine / pharmacology Cells, Cultured Cholera Toxin / pharmacology Colforsin / pharmacology* Cyclic AMP / metabolism* Dexamethasone / pharmacology Dinoprostone / pharmacology Female Fibroblasts / drug effects Fibroblasts / metabolism Gene Expression* Hepatocyte Growth Factor / biosynthesis* Humans Infant Kinetics Protein Kinase C / metabolism RNA, Messenger / biosynthesis* Recombinant Proteins / pharmacology Skin / metabolism* Tetradecanoylphorbol Acetate / pharmacology Transforming Growth Factor beta / pharmacology
IF 3.309
Times Cited 56
Human and Animal Cells