TRANSFORMING GROWTH-FACTOR-ALPHA EXPRESSION DURING LIVER-REGENERATION AFTER PARTIAL-HEPATECTOMY AND TOXIC INJURY, AND POTENTIAL INTERACTIONS BETWEEN TRANSFORMING GROWTH-FACTOR-ALPHA AND HEPATOCYTE GROWTH-FACTOR

Transforming growth factor-alpha and hepatocyte growth factor are important stimulators of hepatocyte proliferation. In this series of experiments we sought to measure the expression of transforming growth factor-alpha mRNA by hepatocytes in response to toxic liver injury produced by carbon tetrachloride or galactosamine and to perform a more detailed analysis of transforming growth factor-alpha expression after partial hepatectomy. We also explored the interactions of transforming growth factor-alpha and hepatocyte growth factor in their effects on hepatocytes in vitro and tested the ability of these factors to stimulate endogenous transforming growth factor-alpha production by hepatocytes. In previous work we have used oligonucleotide probes to measure transforming growth factor-alpha mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-alpha cDNA probe and found that the level of liver transforming growth factor-alpha mRNA increases 4 hr after partial hepatectomy, shows peak expression at 18 hr and returns to the normal level by 36 to 48, hr. Measurement of the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-alpha rises by 12 hr, peaks at 24 hr and remains significantly increased at 48 hr compared with the levels in sham-operated rats. Carbon tetrachloride and galactosamine are known to produce different patterns of acute liver injury, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respectively. After carbon tetrachloride administration the profiles of the transforming growth factor-alpha and hepatocyte growth factor mRNA expression are similar, each showing two peaks: the first at 12 hr and the second at 48 hr. In contrast, after galactosamine-induced liver injury the expression patterns of transforming growth factor-alpha and hepatocyte growth factor mRNAs differ. hepatocyte growth factor shows a major peak at 24 hr, with a smaller increase at 5 days, whereas transforming growth factor-alpha begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transforming growth factor-alpha and hepatocyte growth factor appear to have complementary effects. The maximal hepatocyte nuclear labeling index induced by hepatocyte growth factor was 42%; the addition of transforming growth factor-alpha increased this to 74%. Exogenous transforming growth factor-alpha, but not hepatocyte growth factor, stimulates the production of the transforming growth factor-alpha peptide by hepatocytes. However, when hepatocyte growth factor is added to cultures already containing transforming growth factor-alpha it further increases the amount of transforming growth factor-alpha-stimulated transforming growth factor-alpha synthesis by approximately 40%. These results strengthen the view that transforming growth factor-alpha is an important physiological stimulator of hepatocyte replication in liver growth induced by partial hepatectomy and toxic injury and that hepatocyte growth factor may modulate hepatocyte transforming growth factor-alpha secretion.