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 prostagl andins (PGs) and catecholamines may have a role in promoting hepatocyt e proliferation, and PGE2 and PGF2alpha have also been implicated as m ediators of the mitogenic actions of epidermal growth factor (EGF) (an d transforming growth factor alpha [TGFalpha]). We have studied the ef fects of PGs and norepinephrine on DNA synthesis in serum-free primary cultures of rat hepatocytes, and compared the PG effects with those o f norepinephrine. PGE2, PGF2alpha, PGD2, and the synthetic analog dime thyl-PGE, markedly enhanced the DNA synthesis. A more quantitative ana lysis of the effects of PGE, and PGF2alpha on the DNA synthesis, in th e presence and absence of EGF, indicated that these PGs interacted in an essentially multiplicative manner with the effect of EGF. The effec ts of PGE, and PGF2alpha showed almost complete additivity with the st imulation of DNA synthesis produced by maximally effective concentrati ons of norepinephrine. The data suggest a) that PGE2 and PGF2alpha fac ilitate 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) 19 94 Wiley-Liss, Inc.