Transforming growth factor a (TGF-,) is a growth factor with multiple biological properties including stimulation and inhibition of cell proliferation. To determine whether TGF-P is involved in hepatocyte growth responses in vivo, we measured the levels of TGF-8 mRNA in normal liver and during liver regeneration after partial hepatectomy in rats. TGF-8 mRNA increases in the regenerating liver and reaches a peak (about 8 times higher than basal levels) after the major wave of hepatocyte cell division and mitosis have taken place and after the peak expression of the ras protooncogenes. Although hepatocytes from normal and regenerating liver respond to TGF-fi, they do not synthesize TGF-0 mRNA.Instead, the message is present in liver nonparenchymal cells and is particularly abundant in cell fractions enriched for endothelial cells. TGF-8 inhibits epidermal growth factorinduced DNA synthesis in vitro in hepatocytes from normal or regenerating liver, although the dose-response curves vary according to the culture medium used. We conclude that TGF-P may function as the effector of an inhibitory paracrine loop that is activated during liver regeneration, perhaps to prevent uncontrolled hepatocyte proliferation.The regenerating rat liver is an ideal model system in which to study the mechanisms that control cell proliferation. Under normal physiological conditions, adult rat hepatocytes rarely divide. However, in response to tissue injury or surgical removal of portions of the liver (partial hepatectomy), mature hepatocytes undergo a partially synchronous wave of DNA replication followed by cell division. After partial hepatectomy in rats, the major wave of DNA synthesis starts -14 hr after the operation and reaches a peak at 24 hr. The mass of the liver remnant doubles in the first 36 hr of the growth process, and within a week the normal liver mass is fully restored and the quiescent state reestablished (1, 2). The factors that control this precisely regulated growth process are not known but are often assumed to involve the turning on and off of a positive stimulus for cell proliferation. More likely, however, is the possibility that this tight regulation requires an interplay between growth-stimulatory factors, operative in the early prereplicative stage of the regenerative process, and inhibitory factors, which may be important in later stages as cell division ceases. We have suggested that when quiescent hepatocytes enter the cell cycle, progression to DNA synthesis is controlled by events specifically occurring in the liver-that is, by autocrine or paracrine secretion of growth-stimulatory and -inhibitory factors by hepatic cells (3, 4).It has been shown by several laboratories that transforming growth factor /3 (TGF-f3) is a potent inhibitor of hepatocyte proliferation in vitro (5-7). Under serum-free conditions, as little as 0.1 ng of TGF-,3 per ml (4 pM) causes 85-90% inhibition of epidermal growth factor (EGF)-induced DNA synthesis of hepatocytes in primary culture. TGF-/3 is a 25-kDa, dimeric peptide...

We investigated whether transforming growth factor a (TGF-a) is involved in hepatocyte growth responses both in vivo and in culture. During liver regeneration after partial hepatectomy in rats, TGF-a mRNA increased; it reached a maximum (--9-fold higher than normal) at the peak of DNA synthesis. The message and the peptide were localized in hepatocytes and found in higher amounts in hepatocytes obtained from regenerating liver. TGF-a caused a 13-fold elevation of DNA synthesis in hepatocytes in primary culture and was slightly more effective than epidermal growth factor.TGF-f8 blocked TGF-a stimulation when added either simultaneously with TGF-a or a day later. TGF-a message increased in hepatocytes stimulated to undergo DNA synthesis by TGF-a or epidermal growth factor, and the peptide was detected in the culture medium by RIA. In the regenerating liver, the increase in TGF-a mRNA during the first day after partial hepatectomy coincided with an increase in epidermal growth factor/TGF-a receptor mRNA and a decrease (already reported) in the number of these receptors. We conclude that TGF-a may function as a physiological inducer ofhepatocyte DNA synthesis during liver regeneration by means of an autocrine mechanism and that its stimulatory effects in this growth process are balanced by the inhibitory action of TGF-,B1.

No abstract