INHIBITION OF TRANSFORMING GROWTH-FACTOR-BETA-1 AND UV LIGHT-INDUCED APOPTOSIS BY PROSTANOIDS IN PRIMARY CULTURES OF RAT HEPATOCYTES

Treatment of rat hepatocytes cultured in collagen gel with transformin g growth factor-beta 1 (TGF beta 1) or with UV light strongly increase d 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 we re determined, respectively. DNA of the treated cells showed internucl eosomal DNA fragmentation. Already the presence of the cytokine for on ly 1 h significantly induced apoptosis. The prostanoids PGI(2), PGD(2) , and PGE(1) decreased the frequency of apoptotic nuclei in a dose-dep endent manner by up to 70 to 80% and suppressed internucleosomal DNA f ragmentation. In contrast, PGE(2) and PGF(2 alpha) elicited a smaller protective effect and arachidonic acid had none. In the case of PGE, i t was shown that the prostaglandin was most effective when added toget her 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. Howeve r, 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 p rocesses in the liver. (C) 1998 Academic Press.