TRANSFORMING GROWTH-FACTOR-ALPHA EXPRESSION DURING LIVER-REGENERATIONAFTER 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 impo rtant stimulators of hepatocyte proliferation. In this series of exper iments we sought to measure the expression of transforming growth fact or-alpha mRNA by hepatocytes in response to toxic liver injury produce d by carbon tetrachloride or galactosamine and to perform a more detai led analysis of transforming growth factor-alpha expression after part ial hepatectomy. We also explored the interactions of transforming gro wth factor-alpha and hepatocyte growth factor in their effects on hepa tocytes 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 trans forming growth factor-alpha mRNA expression after partial hepatectomy. In this study we used a rat transforming growth factor-alpha cDNA pro be and found that the level of liver transforming growth factor-alpha mRNA increases 4 hr after partial hepatectomy, shows peak expression a t 18 hr and returns to the normal level by 36 to 48, hr. Measurement o f the corresponding peptide in the liver by means of radioimmunoassay shows that the level of transforming growth factor-alpha rises by 12 h r, peaks at 24 hr and remains significantly increased at 48 hr compare d with the levels in sham-operated rats. Carbon tetrachloride and gala ctosamine are known to produce different patterns of acute liver injur y, with maximal hepatocyte DNA synthesis at 48 hr and 5 days, respecti vely. After carbon tetrachloride administration the profiles of the tr ansforming growth factor-alpha and hepatocyte growth factor mRNA expre ssion 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 hepat ocyte growth factor mRNAs differ. hepatocyte growth factor shows a maj or peak at 24 hr, with a smaller increase at 5 days, whereas transform ing growth factor-alpha begins to increase after 2 days, with a single peak occurring at 5 days. In primary hepatocyte cultures, transformin g growth factor-alpha and hepatocyte growth factor appear to have comp lementary effects. The maximal hepatocyte nuclear labeling index induc ed by hepatocyte growth factor was 42%; the addition of transforming g rowth factor-alpha increased this to 74%. Exogenous transforming growt h factor-alpha, but not hepatocyte growth factor, stimulates the produ ction of the transforming growth factor-alpha peptide by hepatocytes. However, when hepatocyte growth factor is added to cultures already co ntaining transforming growth factor-alpha it further increases the amo unt 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 physio logical stimulator of hepatocyte replication in liver growth induced b y partial hepatectomy and toxic injury and that hepatocyte growth fact or may modulate hepatocyte transforming growth factor-alpha secretion.