In vitro DNA synthesis of mouse hepatocytes stimulated by tumor necrosis factor is inhibited by glucocorticoids and prostaglandin D2 but enhanced by retinoic acid.

We have recently shown that TNF is produced in liver rapidly after partial hepatectomy and that TNF can stimulate DNA synthesis of hepatocyte primary culture with its inhibition by interleukin 6 and transforming growth factor-beta, indicating a pivotal role of TNF and TNF-driven cytokine induction in liver regeneration. We here examined the effects of biological or inflammatory mediators of low molecular weight on the in vitro DNA synthesis of hepatocytes stimulated by TNF. Simultaneous addition of dexamethasone markedly suppressed the growth-stimulating action of TNF, maximally at 10(-7) M and effectively at about 10(-8) M. However, the growth-stimulating effect of EGF was not affected by dexamethasone at all. Physiological glucocorticoids, corticosterone, and hydrocortisone showed virtually the same effect, but other steroid hormones, beta-estradiol, or progesterone did not. Retinoic acid at 10(-7) M, however, enhanced TNF-stimulated hepatocyte DNA synthesis and even more effectively the growth response to EGF. PGD2 at 20 microM was markedly suppressive but PGE2 was not. The addition of indomethacin enhanced the hepatocyte in vitro growth by TNF and EGF at 2-20 microM. These results indicate that the growth of hepatocytes stimulated by TNF is up- and down-regulated by inflammatory mediators and hormones as well as cytokines and suggest the biological significance of TNF and TNF-driven inflammatory reactions in liver regeneration.