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 throu gh its ability to induce the expression of inflammatory and cytotoxic media tors. TNF-alpha is also involved in cell growth accompanying the healing pr ocess in multiple organ systems and influences liver repair following hepat otoxic damage or regeneration following partial hepatectomy. In this respec t, TNF-alpha is a known mitogen for hepatocytes, In this paper me describe a novel role for TNF-alpha in the modulation of expression of TGF-alpha, th e latter being a complete hepatocyte mitogen, TNF-alpha directly up-regulat es TGF-alpha mRNA by up to 7-fold in isolated mouse hepatocytes, whereas ne utralization of TNF-alpha significantly decreased liver mRNA and protein ex pression of TGF-alpha following chemical-induced hepatotoxicity. That TNF-a lpha directly stimulated TGF-alpha was suggested by the inability of either anti-IL-6 Abs or cycloheximide to inhibit TNF-alpha-induced TGF-alpha expr ession in hepatocytes. However, in the presence of anti-TGF-alpha neutraliz ing Abs, the mitogenic activity of TNF-alpha is abrogated. Using cells tran sfected with the TGF-alpha promoter, and an RNA polymerase inhibitor, it wa s shown that TNF-alpha modulates TGF-alpha expression through both pre- and posttranscriptional events. Taken together, these data suggest that TNF-al pha participates in liver repair and regeneration, in part, by directly ind ucing the expression of TGF-alpha.