BIDIRECTIONAL EFFECTS OF KUPFFER CELLS ON HEPATOCYTE PROLIFERATION INVITRO

The control of rat hepatocyte DNA synthesis in vitro by Kupffer cells and transformed perisinusoidal lipocytes, i.e. myofibroblast-like cells was studied. Conditioned media from Kupffer cells inhibit the replicative (hydroxyurea-sensitive) DNA synthesis dose-dependently in primary cultures of hepatocytes stimulated by epidermal growth factor (EGF). The cytokine responsible for the inhibition was identified as transforming growth factor beta (TGF-beta). After neutralization of activated TGF-beta in these media, DNA synthesis is stimulated in quiescent hepatocytes via transforming growth factor alpha (TGF-alpha) demonstrated by competitive TGF-alpha/EGF-receptor blocking on hepatocytes. Results similar to those obtained with Kupffer cells were found with conditioned media of myofibroblast-like cells. Northern blot hybridization confirms the expression of both TGF-beta and TGF-alpha in Kupffer cells and myofibroblast-like cells, respectively. These findings support the notion that Kupffer cells and myofibroblast-like cells might regulate in both directions liver regeneration depending on the proportion of secreted TGF-alpha and TGF-beta and on the activation status of TGF-beta, of which a significant fraction is secreted in the latent form.