Foxa1 and Foxa2 regulate bile duct development in mice Mario Strazzabosco  Journal of Hepatology  Volume 52, Issue 5, Pages 765-767 (May 2010) DOI: 10.1016/j.jhep.2009.12.022 Copyright © 2010 European Association for the Study of the Liver Terms and Conditions

Fig. 1 Ductular proliferation and the expansion of “reactive cholangiocytes” is a common compensatory and reparative response to liver damage (A). Reactive cholangiocytes, also called “liver progenitor cells” because of their ability to differentiate into hepatocytes, are thought to originate from epithelial cells lining cholangioles and ducts of Hering. Reactive cholangiocytes generate a number of growth factors, chemokines, and cytokines generating a network of autocrine and paracrine signals that play a key role in liver repair and cross talk with the other cell types of the hepatic reparative complex (mesenchymal cells, inflammatory cells, endothelial cells) (B). The molecular mechanisms regulating the activation of reactive cholangiocytes are not known. The paper from Li et al. begins to shed light on these mechanisms showing that release of Foxa1/2 repression is essential to allow transcription of IL-6 in developing and reactive biliary cells. Foxa1/2 are “pioneer” factors, able to open the chromatin and enhance the binding of other transcription factors, such as the glucocorticoid receptor (GR), to their target genes. The IL-6 promoter contains closely spaced binding sites for Foxa1/2, GR, and NF-κB. GR suppresses the IL-6 promoter. Li et al. showed that Foxa1/2 are required to enable the GR to bind to the interlukin-6 (IL-6) promoter. In their absence, NF-κB, will bind to the IL-6 promoter instead of GR, resulting in stimulation of IL-6 production. It is tempting to speculate that similar models may apply to several of the other paracrine and autocrine factors generated by reactive cells (C). Journal of Hepatology 2010 52, 765-767DOI: (10.1016/j.jhep.2009.12.022) Copyright © 2010 European Association for the Study of the Liver Terms and Conditions