ABSTRACT
Previously, we have observed that epidermal growth factor (EGF), a potent mitogen for cultured hepatocytes, stimulates the production of IGF-I and IGF-binding proteins (IGFBPs) by cultured hepatocytes from adult rats. This study was undertaken to investigate the possibility that other growth factors of hepatic origin could specifically be involved in the regulation of IGF-I and IGFBP expression. The effects of transforming growth factor-alpha (TGF-alpha), through EGF receptors to induce a mitogenic response, and transforming growth factor-beta1 (TGF-beta1), produced by non-parenchymal liver cells and able to inhibit hepatocyte proliferation in vivo and in culture, have been studied in cultured adult rat hepatocytes. Our results demonstrate that TGF-alpha and TGF-beta1 significantly stimulate IGF-I and IGFBP secretion by cultured hepatocytes but no change in the abundance of IGF-I and IGFBP mRNAs was observed with respect to controls. Cycloheximide is able to inhibit both basal and TGF-stimulated release of IGF-I and a similar effect was elicited by octreotide, the somatostatin analog, known to directly affect hepatic IGF-I gene expression. Our findings show the role of the liver in the secretion of IGF-I and IGFBPs, not only under endocrine and nutritional control but also under autocrine and paracrine control.
Subject(s)
Insulin-Like Growth Factor I/metabolism , Liver/drug effects , Transforming Growth Factor alpha/pharmacology , Transforming Growth Factor beta/pharmacology , Animals , Cells, Cultured , Cycloheximide/pharmacology , Dose-Response Relationship, Drug , Insulin-Like Growth Factor Binding Proteins/genetics , Insulin-Like Growth Factor Binding Proteins/metabolism , Insulin-Like Growth Factor I/genetics , Liver/metabolism , Male , Octreotide/pharmacology , RNA/analysis , Rats , Rats, Wistar , Up-RegulationABSTRACT
In this study we employed primary culture of adult rat hepatocytes to verify the effects of two different extracellular matrices (collagen, matrigel) on EGF-stimulated DNA synthesis and c-myc expression. Our results confirm that in adult rat hepatocytes EGF induces DNA synthesis, preceded by a transient increase of c-myc expression, when cells are cultured at low density on collagen. DNA synthesis appears to be in reciprocal relationship with hepatic expression of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-4, suggesting that IGF-I/IGFBPs system is not involved in liver growth.
Subject(s)
Cell Culture Techniques/methods , DNA/biosynthesis , Epidermal Growth Factor/biosynthesis , Liver/cytology , Animals , Cell Count , Cells, Cultured , Collagen/metabolism , Drug Combinations , Extracellular Matrix/metabolism , Laminin/metabolism , Liver/metabolism , Male , Proteoglycans/metabolism , Proto-Oncogene Proteins c-myc/biosynthesis , RNA, Messenger/biosynthesis , Rats , Rats, WistarABSTRACT
Gammaglutamyltranspeptidase (GGT) activity is considered as a marker of liver phenotype, being maximally expressed in fetal liver and virtually absent in adult mature tissue. Since thyroid hormone has been identified to influence growth and development of almost all tissues, we have investigated the possible involvement of such factors in regulating rat hepatic GGT. Our results indicate that the activity of GGT in liver of perinatal hypothyroid rats is low as well as in control animals; instead, it is greatly increased in adult hypothyroid rats compared to controls of the same age (+260% in 2-month-old hypothyroid rats). Replacement therapy with T3 to hypothyroid rats normalizes the enzyme activity to the levels of control animals. Thyroid hormone appears to modulate the gene expression of the enzyme, since in the different thyroid status GGT mRNA level closely parallels the variations of the enzyme activity. These results further suggest that thyroid hormone plays a crucial role in maintaining the phenotype of adult liver tissue.
Subject(s)
Gene Expression Regulation , Liver/enzymology , Thyroid Hormones/physiology , gamma-Glutamyltransferase/genetics , Animals , Hypothyroidism/chemically induced , Hypothyroidism/drug therapy , Hypothyroidism/enzymology , Liver/drug effects , Male , Methimazole , RNA, Messenger/metabolism , Rats , Rats, Wistar , Thyroxine/blood , Triiodothyronine/blood , Triiodothyronine/therapeutic use , gamma-Glutamyltransferase/metabolismSubject(s)
DNA/biosynthesis , Epidermal Growth Factor/pharmacology , Liver/drug effects , Animals , Biotechnology , Cells, Cultured , DNA Topoisomerases, Type I/metabolism , Gene Expression/drug effects , Genes, myc/drug effects , Insulin-Like Growth Factor I/genetics , Kinetics , Liver/cytology , Liver/metabolism , Poly(ADP-ribose) Polymerases/metabolism , RatsABSTRACT
The aim of this study was to investigate the possible role of epidermal growth factor (EGF) and of insulin-like growth factor-I (IGF-I) in physiological and pathological changes of the endometrial tissue during aging. Thirty-four patients undergoing hysterectomy were divided into three groups: (A) premenopausal women with regular menses, (B) pre-menopausal women with irregular bleeding and (C) post-menopausal women. Endometrial samples were collected after the removal of uterus and were used for immunohistochemical evaluation of EGF, EGF receptor (EGFr) and IGF-I and also for Northern blot analysis of IGF-I gene expression. Plasma levels of 17 beta-oestradiol (E2), D4-androstenedione (D4-A) and oestrone (E1) were also assayed. The immunohistochemical scores (HSCORES) for EGF, EGFr and IGF-I were significantly higher in groups A and B than in group C. Independently from the menstrual history, significantly higher HSCORES of EGF, EGFr and IGF-I were present in hyperplastic endometrium than in those which were proliferative and atrophic. Moreover, IGF-I mRNA expression was observed in all pre-menopausal women, whereas only 1 post-menopausal women with hyperplastic endometrium showed detectable RNA encoding for IGF-I. Higher levels of D4-A were also significantly correlated (P < 0.05) with higher HSCORES of EGF, EGFr and IGF-I. Our results suggest that the above mentioned growth factors could act as mediators of oestrogens on the endometrial functional activity.
