STIMULATION OF HEPATOCYTE DNA-SYNTHESIS BY PROSTAGLANDIN-E(2) AND PROSTAGLANDIN-F(2-ALPHA) - ADDITIVITY WITH THE EFFECT OF NOREPINEPHRINE, AND SYNERGISM WITH EPIDERMAL GROWTH-FACTOR

Previous data obtained in vivo and in vitro suggest that both prostaglandins (PGs) and catecholamines may have a role in promoting hepatocyte proliferation, and PGE2 and PGF2alpha have also been implicated as mediators of the mitogenic actions of epidermal growth factor (EGF) (and transforming growth factor alpha [TGFalpha]). We have studied the effects of PGs and norepinephrine on DNA synthesis in serum-free primary cultures of rat hepatocytes, and compared the PG effects with those of norepinephrine. PGE2, PGF2alpha, PGD2, and the synthetic analog dimethyl-PGE, markedly enhanced the DNA synthesis. A more quantitative analysis of the effects of PGE, and PGF2alpha on the DNA synthesis, in the presence and absence of EGF, indicated that these PGs interacted in an essentially multiplicative manner with the effect of EGF. The effects of PGE, and PGF2alpha showed almost complete additivity with the stimulation of DNA synthesis produced by maximally effective concentrations of norepinephrine. The data suggest a) that PGE2 and PGF2alpha facilitate and synergize with, rather than mediate, the actions of EGF in hepatocytes, and b) that this effect of the PGs occurs by mechanisms that are at least partly distinct from those of norepinephrine. (C) 1994 Wiley-Liss, Inc.