TNF-α Regulates Transforming Growth Factor-α Expression in Regenerating Murine Liver and Isolated Hepatocytes

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Abstract
TNF-α 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-α 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-α is a known mitogen for hepatocytes. In this paper we describe a novel role for TNF-α in the modulation of expression of TGF-α, the latter being a complete hepatocyte mitogen. TNF-α directly up-regulates TGF-α mRNA by up to 7-fold in isolated mouse hepatocytes, whereas neutralization of TNF-α significantly decreased liver mRNA and protein expression of TGF-α following chemical-induced hepatotoxicity. That TNF-α directly stimulated TGF-α was suggested by the inability of either anti-IL-6 Abs or cycloheximide to inhibit TNF-α-induced TGF-α expression in hepatocytes. However, in the presence of anti-TGF-α neutralizing Abs, the mitogenic activity of TNF-α is abrogated. Using cells transfected with the TGF-α promoter, and an RNA polymerase inhibitor, it was shown that TNF-α modulates TGF-α expression through both pre- and posttranscriptional events. Taken together, these data suggest that TNF-α participates in liver repair and regeneration, in part, by directly inducing the expression of TGF-α.