Bidirectional effects of Kupffer cells on hepatocyte proliferation in vitro

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Abstract
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 β (TGFβ). After neutralization of activated TGFβ in these media. DNA synthesis is stimulated in quiescent hepatocytes via transforming growth factor α (TGFα) demonstrated by competitive TGFα/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 TGFβ and TGFα 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 TGFα and TGFβ and on the activation status of TGFβ, of which a significant fraction is secreted in the latent form.