Synergism between interferon-gamma and cAMP in induction of hepatocyte growth factor in human skin fibroblasts.
Interferon (IFN)-gamma stimulates hepatocyte growth factor (HGF) production markedly in various human leukemia cell lines, but its positive effect in human skin fibroblasts is slight. We examined the combined effect of IFN-gamma and various HGF inducers on HGF production in human skin fibroblasts. IFN-gamma synergistically enhanced HGF production stimulated by 8-bromo-cAMP, one of the most effective inducers of HGF: HGF secreted from cells incubated with 1 mM of 8-bromo-cAMP, 1000 U/ml of IFN-gamma and both of these was approximately 8, 1.5 and 24 times, respectively, that secreted from untreated cells. The effect of IFN-gamma was dose-dependent and was nullified by an anti-IFN-gamma antibody. Neither IFN-alpha nor IFN-beta had such an enhancing effect, but both these IFNs inhibited the synergistic effect of IFN-gamma and 8-bromo-cAMP. IFN-gamma also synergistically augmented HGF production induced by interleukin-1beta and cAMP-increasing agents cholera toxin, forskolin and prostaglandin E(2). HGF gene expression upregulated by cholera toxin, forskolin and 8-bromo-cAMP was markedly enhanced by IFN-gamma, which was detected as early as 3 h after its addition. The synergy between HGF inducers and IFN-gamma is not common to all HGF inducers, because HGF production stimulated by epidermal growth factor and protein-kinase-C-activating phorbol esters was significantly inhibited by IFN-gamma. These results indicate that IFN-gamma synergistically stimulates cAMP-induced HGF production and inhibits HGF production induced by growth factors and protein kinase C activators in human skin fibroblasts.
Gohda
E
E
Department of Immunochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama, 700-8530, Japan. gohda@pheasant.pharm.okayama-u.ac.jp
Kuromitsu
K
K
Matsunaga
T
T
Miyazaki
M
M
Yamamoto
I
I
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D004357:Drug Synergism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D007223:Infant; D016899:Interferon-beta / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D012867:Skin / Q000166:cytology; D012879:Skin Physiological Phenomena; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D015124:8-Bromo Cyclic Adenosine Monophosphate; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D016899:Interferon-beta; D007371:Interferon-gamma; D000242:Cyclic AMP; D013755:Tetradecanoylphorbol Acetate