Sensitization by interleukin-6 of rat hepatocytes to tumor necrosis factor α-induced apoptosis

Background/Aims: Tumor necrosis factor (TNF) elicits hepatocyte apoptosis in toxic liver injury and is also central in hepatocyte proliferation after partial hepatectomy. In both circumstances interleukin (IL)-6 levels are also elevated. In mouse liver IL-6 attenuated Fas receptor-mediated apoptosis indicating its interference with pro-apoptotic signal chains. It was, therefore, the aim to examine the modulation by IL-6 of TNFalpha-induced apoptosis in rat hepatocytes. Methods: Primary rat hepatocytes were treated with IL-6 prior to induction of apoptosis with TNFalpha/actinomycin D or anti-Fas antibody M-20. Apoptosis was detected by determination of caspase-3 activation and bisbenzimide staining of condensed nuclei. Expression of TNFalpha receptors was analyzed by semi-quantitative polymerase chain reaction and ligand binding studies with [I-125]-TNFalpha. Results: IL-6 treatment doubled TNFalpha/actinomycin D-induced caspase-3 activity and significantly enhanced chromatin condensation. By contrast IL-6 inhibited Fas-induced increase in caspase-3 activity by 45% and significantly reduced chromatin condensation. IL-6 increased the mRNA level of TNF-R1 1.35-fold and augmented cell surface binding of [I-125]-TNFalpha Mold. The latter and TNFalpha-mediated caspase activation was attenuated by prostaglandin E-2. Conclusions: IL-6-in contrast to its anti-apoptotic modulation of the Fas-induced pathway-exerted a pro-apoptotic effect on the TNFalpha/actinomycin D-induced apoptosis by increasing the number of TNF-R on hepatocytes. (C) 2003 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.