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...

Dipeptidyl peptidase IV (DPPIV) is a serine exoproteinase expressed at high levels in epithelial cells of kidney, liver and small intestine. Recently Watanabe, Kohima & Fujimoto [(1987) Experientia 43, 400-401] and Gossrau et al. [(1990) Histochem. J. 22, 172-173] reported that Fischer 344 rats are deficient in this enzyme. We have examined DPPIV expression in Fischer 344 rats available from U.S. and German suppliers and find that livers of the U.S. Fischer rats, in contrast with their German counterparts, express active DPPIV (D+). Northern analysis of liver RNA showed comparable levels of 3.4 kb and 5.6 kb DPPIV transcripts in both D+ rats from the U.S. and German (D-) rats. Monoclonal antibody (MAb) 236.3 to DPPIV immunoprecipitated at 150 kDa enzymically active (105 kDa, denatured) protein from surface-labelled D+ hepatocytes and reacted with canalicular and sinusoidal membranes (as shown by immunofluorescence microscopy). MAb 236.3 failed to immunoprecipitate a labelled peptide from D- cell extract or to stain D- liver sections. Polyclonal antibody (PAb) specific for DPPIV immunoprecipitated an enzymically active peptide from D+ hepatocyte extracts and a smaller, inactive peptide from D- hepatocyte extracts. Peptide maps of DPPIV immunoprecipitated from D+ extracts with MAb 236.3 and PAb were identical, but differed from that of the D- hepatocyte component recognized by PAb. The molecular basis of the DPPIV deficiency in the D- rats thus appears to be the translation of an enzymically inactive protein missing the epitope recognized by MAb 236.3. We have exploited these D- rats as hosts for syngeneic transplantation of liver cells from D+ Fischer rats. DPPIV expression is stable in the transplanted cells and allows them to be readily distinguished from the surrounding D- tissue.