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.
Kroll
B
B
GSF-Forschungszentrum für Umwelt und Gesundheit, Institut für Toxikologie, Neuherberg, D-85758, Germany.
Kunz
S
S
Tu
N
N
Schwarz
L R
LR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D008297:Male; D011453:Prostaglandins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
D011453:Prostaglandins; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D007770:L-Lactate Dehydrogenase