Inhibition of transforming growth factor-β1 and UV light-induced apoptosis by prostanoids in primary cultures of rat hepatocytes

Treatment of rat hepatocytes cultured in collagen gel with transforming growth factor-beta 1 (TGF beta 1) or with UV light strongly increased the frequency of apoptotic nuclei within 24 h; at doses of 0.5 ng/ml TGF beta 1 or 90 J/m(2) UV light about 17 and 22% apoptotic nuclei were determined, respectively. DNA of the treated cells showed internucleosomal DNA fragmentation. Already the presence of the cytokine for only 1 h significantly induced apoptosis. The prostanoids PGI(2), PGD(2), and PGE(1) decreased the frequency of apoptotic nuclei in a dose-dependent manner by up to 70 to 80% and suppressed internucleosomal DNA fragmentation. In contrast, PGE(2) and PGF(2 alpha) elicited a smaller protective effect and arachidonic acid had none. In the case of PGE, it was shown that the prostaglandin was most effective when added together with TGF beta 1 or within 2 h before or after treatment with this cytokine. An early increase of the tumor supressor gene product p53 is thought to play a decisive role in UV light-induced apoptosis. However, this increase in p53 was not affected by the strong cytoprotective prostacyclin PGI(2). Our findings show a marked antiapoptotic activity of the prostanoids PGE(1), PGI(2), and PGD(2) and raise the question of whether these prostanoids may influence apoptosis in pathological processes in the liver. (C) 1998 Academic Press.