Roles of TNF-α in ductular metaplasia of hepatocytes

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There have been several lines of evidence showing that mature hepatocytes can transdifferentiate into bile ductular cells both in vivo and in vitro, although the mechanism is unclear. We examined whether cytokines produced by Kupffer cells affected the phenotype of hepatocytes in a three-dimensional culture system. Here, we report that tumor necrosis factor α (TNF-α) is a cytokine which strongly induces bile ductular differentiation of hepatocytes. Spheroidal aggregates of rat hepatocytes were embedded within a type I collagen gel matrix and cultured in the presence of various cytokines. Among those tested, TNF-α inhibited albumin expression, while enhanced the expression of cytokeratin 19 (CK19) and spermatogenic immunoglobulin superfamily (SgIGSF). After 2 to 3 weeks in the presence of TNF-α, hepatocytic spheroids were transformed into extensively branching tubular structures composed of CK19-positive cells. These cells responded to secretin with an increased secretion and expressed functional bile duct markers. TNF-α induced phosphorylation of Jun N-terminal kinase (JNK) and c-Jun, and the morphogenesis was inhibited by a JNK inhibitor. When these ductular cells were retrieved from gels by collagenase digestion and cultured on Matrigel, they gradually recovered hepatocytic phenotype. Our results suggest that TNF-α promote ductular differentiation of hepatocytes via the JNK-c-Jun pathway and that the transdifferentiation is at least partly reversible.