Modulation of insulin-like growth factor-II/mannose 6-phosphate receptors and transforming growth factor-beta 1 during liver regeneration.

Transforming growth factor-beta 1 (TGF-beta 1) is a potent mito-inhibiting substance that is thought to play an important function in regulating hepatocyte proliferation during liver regeneration. In this investigation, we have shown by immunohistochemistry that hepatocytes containing significant intracellular concentrations of TGF-beta 1 12 h after a two-thirds partial hepatectomy. This increase in hepatocyte TGF-beta 1 concentration was initially confined to those cells that resided in the periportal region of the liver. The elevation of intracellular TGF-beta 1 was, however, transient, and within 36 h, the hepatocytes positive for TGF-beta 1 had changed in a wavelike fashion from the periportal to the pericentral region of the liver lobules. By 48 h, most hepatocytes no longer contained TGF-beta 1. Interestingly, this temporary increase in TGF-beta 1 always preceded the onset of hepatocyte replication by approximately 3-6 h. Since TGF-beta 1 mRNA has been shown to be absent from hepatocytes normally and throughout liver regeneration, these results imply that the increase in intracellular TGF-beta 1 resulted from an augmented uptake. We have further shown that the insulin-like growth factor-II/mannose 6-phosphate (IGF-II/Man-6-P) receptors were up-regulated during liver regeneration and that the increased expression of this receptor co-localized in those hepatocytes containing elevated concentrations of TGF-beta 1. The latent TGF-beta 1 phosphomannosyl glycoprotein complex has been shown to bind to the IGF-II/Man-6-P receptor. Therefore, our data are consistent with the hypothesis that this latent complex is internalized through the IGF-II/Man-6-P receptor to the intracellular acidic prelysosomal/endosomal compartments where the mature TGF-beta 1 molecule could be activated by dissociation from the latent complex.