Transforming growth factor alpha may be a physiological regulator of liver regeneration by means of an autocrine mechanism.

Abstract

We investigated whether transforming growth factor .alpha. (TGF-.alpha.) is involved in hepatocyte growth responses both in vivo and in culture. During liver regeneration after partial hepatectomy in rats, TGF-.alpha. mRNA increased; it reached a maximum (.apprxeq. 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-.alpha. caused a 13-fold elevation of DNA synthesis in hepatocytes in primary culture and was slightly more effective than epidermal growth factor. TGF-.beta. blocked TGF-.alpha. stimulation when added either simultaneously with TGF-.alpha. or a day later. TGF-.alpha. message increased in hepatocytes stimulated to undergo DNA synthesis by TGF-.alpha. or epidermal growth factor, and the peptide was detected in the culture medium by RIA. In the regenerating liver, the increase in TGF-.alpha. mRNA during the first day after partial hepatectomy coincided with an increase in epidermal growth factor/TGF-.alpha. receptor mRNA and a decrease (already reported) in the number of these receptors. We conclude that TGF-.alpha. may function as a physiological inducer of hepatocyte 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-.beta.1.