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Epidermal growth factor and transforming growth factor alpha stimulated DNA synthesis in primary cultures of adult rat hepatocytes. In the presence of neurotensin, the stimulatory effect of epidermal growth factor or transforming growth factor alpha on DNA synthesis was enhanced 3- to 5-fold. Since neurotensin by itself did not stimulate DNA synthesis at all concentrations tested, enhancement of DNA synthesis by neurotensin is due to the amplification of the effect of epidermal growth factor or transforming growth factor alpha. The amplification by neurotensin was observed in a dose-dependent manner with a maximal effect at 10(-8)M, although its effect was significantly observed at as low as 10(-10) M. This neurotensin amplification of DNA synthesis was observed when hepatocytes were cultured in Williams' medium E, but not in Leibovitz L-15 medium, suggesting that minor components in the medium are required for hepatocytes to fully respond to neurotensin. Neurotensin-related peptides such as kinetensin or neuromedin-N did not have this amplifying effect on DNA synthesis at any concentration tested. From these results, neurotensin can be regarded as a new secondary mitogen.

Neurotensin-Amplification of DNA Synthesis Stimulated by EGF or TGF.ALPHA. in Primary Cultures of Adult Rat Hepatocytes.