TNF-alpha regulates transforming growth factor-alpha expression in regenerating murine liver and isolated hepatocytes

TNF-alpha is a pleotropic proinflammatory cytokine that has been implicated as a contributing factor in a number of disease processes, primarily through its ability to induce the expression of inflammatory and cytotoxic mediators. TNF-alpha is also involved in cell growth accompanying the healing process in multiple organ systems and influences liver repair following hepatotoxic damage or regeneration following partial hepatectomy. In this respect, TNF-alpha is a known mitogen for hepatocytes. In this paper we describe a novel role for TNF-alpha in the modulation of expression of TGF-alpha, the latter being a complete hepatocyte mitogen. TNF-alpha directly up-regulates TGF-alpha mRNA by up to 7-fold in isolated mouse hepatocytes, whereas neutralization of TNF-alpha significantly decreased liver mRNA and protein expression of TGF-alpha following chemical-induced hepatotoxicity. That TNF-alpha directly stimulated TGF-alpha was suggested by the inability of either anti-IL-6 Abs or cycloheximide to inhibit TNF-alpha-induced TGF-alpha expression in hepatocytes. However, in the presence of anti-TGF-alpha neutralizing Abs, the mitogenic activity of TNF-alpha is abrogated. Using cells transfected with the TGF-alpha promoter, and an RNA polymerase inhibitor, it was shown that TNF-alpha modulates TGF-alpha expression through both pre- and posttranscriptional events. Taken together, these data suggest that TNF-alpha participates in liver repair and regeneration, in part, by directly inducing the expression of TGF-alpha.