Figure 1.

STAT3 signaling in hepatocytes. Hepatocytes express high levels of gp130, which is a common signal chain for IL-6 and IL-6 family cytokines, high levels of IL-6 receptors and various corresponding receptors for IL-6 family cytokines. IL-6 family cytokines include leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM), cardiotrophin-1 (CT-1), and IL-11. The ligation of these cytokines (IL-6 and IL-6 family cytokines) with their corresponding receptors leads to the dimerization of gp130, followed by dimerization of gp130-associated Janus kinases (JAKs) and phosphorylation of JAKs and gp130. This receptor-kinase complex then recruits and phosphorylates cytoplasmic protein STAT3. Phosphorylated STAT3 forms a dimer, translocates into the nuclei and subsequently induces transcription of many genes. Hepatocytes also express high levels of IL-22R1 and IL-10R2 for IL-22 signaling. IL-6, IL-6 family cytokines, and IL-22 predominantly activate STAT3, but also induce a weak activation of other STATs and MAP kinases. Human hepatocytes express high levels of IFNAR1 and functional IFNAR2c (while mouse and rat hepatocytes predominantly express inhibitory IFNAR2a and poorly respond to IFN-α stimulation). IFN-α/β predominately induce STAT1 activation in primary human hepatocytes but also induce strong STAT3 activation. Activated STAT3 induces transcription of many genes that play important roles in inducing acute phase responses, promoting hepatocyte survival and liver regeneration, and ameliorating fatty liver.