Signal transducer and activator of transcription 3 in liver diseases: a novel therapeutic target

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is activated by many cytokines and growth factors and plays a key role in cell survival, proliferation, and differentiation. STAT3 activation is detected virtually in all rodent models of liver injury and in human liver diseases. In this review, we highlight recent advances of STAT3 signaling in liver injury, steatosis, inflammation, regeneration, fibrosis, and hepatocarcinogenesis. The cytokines and small molecules that activate STAT3 in hepatocytes may have therapeutic benefits to treat acute liver injury, fatty liver disease, and alcoholic hepatitis, while blockage of STAT3 may have a therapeutic potential to prevent and treat liver cancer.

Keywords: STAT3; STAT3 signaling; liver diseases; liver injury.

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.

Figure 2

STAT3 signaling in Kupffer cells. Kupffer cells express high levels of IL-10R1 and IL-10R2. The ligation of IL-10 with IL-10R1 and IL-10R2 leads to prolonged activation of STAT3, thereby inhibiting inflammatory responses. In contrast, the ligation of IL-6 with IL-6R and gp130, which are expressed at high levels on Kupffer cells, leads to transient activation of STAT3, followed by the induction of inflammatory responses. STAT3 activation induces expression of SOCS3, which in turns inhibits IL-6 activation of STAT3, but does not inhibit IL-10 signaling.

Figure 3

STAT3 signaling in hepatic stellate cells. Hepatic stellate cells express high levels of the long form of the leptin receptor (OBRL). The ligation of leptin with OBRL induces activation of STAT3, leading to stellate cell activation, proliferation, and survival. IL-6 can also stimulate stellate cell survival, proliferation, and activation via binding of IL-6R and gp130 on stellate cells.