Modulation of hepatic lipocyte proteoglycan synthesis and proliferation by Kupffer cell-derived transforming growth factors type β1 and type α

Abstract

Soluble mediators elaborated by activated Kupffer cells have been implicated in the activation of liver fat-storing cells. In the present study some of these factors were identified as TGFβ and TGFα affecting disparate reactions in the activation process. TGFβ is secreted in an inactive, latent form by Kupffer cells. It is activated after addition to primary FSC cultures and stimulates dose-dependently sulfated proteoglycan synthesis especially that of chondroitin sulfate, whereas the incorporation of [ 3H] thymidine is reduced significantly. These effects were neutralized completely by anti-TGFβ antibodies which ultimately converted the proliferation inhibitory effect of Kupffer cell medium in a proliferation stimulatory action. The latter is at least partially due to TGFα. Both cytokines are preferentially expressed in activated Kupffer cells. We conclude that Kupffer cells modulate the mitogenic activity of FSC in culture depending on the ratio of activated TGFβ and TGFα and affect chondroitin sulfate synthesis mainly by TGFβ. The results suggest a paracrine activation of FSC in injured liver by both transforming growth factors secreted by activated Kupffer cells.