Stat3 in hepatoprotection

Stat3 is activated by inflammation and various insults in hepatocytes. Important activators are growth factors such as EGF and the cytokine IL-6 (Figure 1). This multifunctional cytokine binds to membrane-anchored IL-6R/gp130 heterodimers on hepatocytes, which activates the Jak/Stat, Ras and Pi3K pathways. IL-6 stimulation leads to phosphorylation of Stat3 at Tyr-705 and subsequent formation of Stat3 homodimers or Stat1/Stat3 heterodimers that enter the nucleus and activate gene transcription. Activation of Stat3 by IL-6 in hepatocytes is considered to be an essential event for hepatoprotection. We are currently investigating the hepatoprotective role of Stat3 in cholestatic diseases (for reference see: Mair et al., Gastroenterology 2010; Mair et al., Frontiers in Bioscience 2011).

Figure 1: Stat3 is activated by various signals in inflammed tissues and cancers. Potent activators are cytokine receptors (IL-6R), receptor-tyrosine kinases (EGFR) and non-receptor-tyrosine kinases (Abl, Src). These signals lead to Stat3 phosphorylation, homodimerization, translocation into the nucleus and Stat3 target gene expression. Stat3 is negatively regulated by Pias3 and SOCS3 which is a Stat3 target gene.