Inhibition of transforming growth factor-beta1 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-beta1 (TGFbeta1) or with UV light strongly increased the frequency of apoptotic nuclei within 24 h; at doses of 0.5 ng/ml TGFbeta1 or 90 J/m2 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 PGI2, PGD2, and PGE1 decreased the frequency of apoptotic nuclei in a dose-dependent manner by up to 70 to 80% and suppressed internucleosomal DNA fragmentation. In contrast, PGE2 and PGF2alpha elicited a smaller protective effect and arachidonic acid had none. In the case of PGE1 it was shown that the prostaglandin was most effective when added together with TGFbeta1 or within 2 h before or after treatment with this cytokine. An early increase of the tumor suppressor 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 PGI2. Our findings show a marked antiapoptotic activity of the prostanoids PGE1, PGI2, and PGD2 and raise the question of whether these prostanoids may influence apoptosis in pathological processes in the liver.