Activin A and hepatocyte growth regulation

The present study was conducted to examine the effect of activin A on growth of rat hepatocytes. EGF induced a 10‐fold increase in DNA synthesis as assessed by [³H]thymidine incorporation in cultured hepatocytes. When activin A was added together with EGF, DNA synthesis induced by EGF was markedly inhibited. Inhibition was detected at a concentration of 10⁻¹⁰ M, and 5×10⁻⁹ M activin A almost completely blocked EGF‐mediated DNA synthesis. Similarly, activin A completely blocked DNA synthesis induced by hepatocyte growth factor/scatter factor. Activin A was capable of inhibiting EGF‐mediated DNA synthesis, even when added 36 h after the addition of EGF. With the same time interval, TGF‐β also blocked EGF‐induced DNA synthesis. Although both activin A and TGF‐β inhibited growth of hepatocytes in a similar manner, either activin A or TGF‐β did not compete with each other in their binding when assessed by competitive binding using an iodinated ligand. When hepatocytes were incubated with EGF, release of bioactivity of activin A into culture medium was detected after 48 h or later. Activity of activin A was released from parenchymal cells but not from non‐parenchymal cells. mRNA for β_A subunit of activin was detected only slightly in unstimulated hepatocytes, but markedly increased at 48 h after the addition of EGF. To determine whether endogenously produced activin A affects DNA synthesis, we examined the effect of follistatin, an activin‐binding protein that blocks the action of activin A. An addition of follistatin significantly enhanced EGF‐induced DNA synthesis. Finally, in partial hepatectomized rat, expression of mRNA for β_A subunit in liver was markedly increased 24 h after the partial hepatectomy. These results indicate that activin A inhibits initiation of DNA synthesis in hepatocytes by acting on its own receptor and that activin A acts as an autocrine inhibitor of DNA synthesis in rat hepatocytes.