IL-8 induces transdifferentiation of mature hepatocytes toward the cholangiocyte phenotype

The adult mammalian liver exhibits a remarkable regenerative capacity, with different modes of regeneration according to the type and extent of injury. Hepatocyte-cholangiocyte biphenotypic liver progenitor cell populations appear under conditions of excessive injury. It has been reported that mature hepatocytes can transdifferentiate toward a cholangiocyte phenotype and be a cellular source of progenitor cell populations. Here, we determined that among various plasma cytokines, interleukin (IL)-8 levels were significantly elevated in acute liver failure and severe acute liver injury patients. In vitro assays revealed that administration of IL-8 homologues increases the expression of Sry HMG box protein 9 (SOX9). In liver biopsies of acute liver injury patients, we observed the appearance of SOX9-positive biphenotypic hepatocytes accompanied by elevation of plasma IL-8 levels. Our results suggest that IL-8 regulates the phenotypic conversion of mature hepatocytes toward a cholangiocyte phenotype.