Chronic alcohol drinking is a major cause of chronic liver disease worldwide and encompasses

a spectrum of liver injuries, including fatty liver, alcoholic hepatitis, drug discovery cirrhosis, and hepatocellular carcinoma.[1, 2] Many mechanisms underlying the pathogenesis of alcoholic liver disease (ALD) have been identified.[1, 2] These include direct hepatotoxicity of ethanol and its metabolites, oxidative stress generated by ethanol metabolism, activation of innate immunity, elevation of pro-inflammatory cytokines and chemokines, and many other mechanisms. Among the cytokines and chemokines involved in progression of ALD, tumor necrosis factor-α and monocyte chemoattractant protein-1 have been shown to play an important role in the development of early alcoholic liver injury,[3,

4] whereas interleukin-6 (IL-6), via the activation of signal transducer and activator of transcription 3 (STAT3) in hepatocytes during early alcoholic liver injury, plays an important role in ameliorating steatosis and hepatocellular damage.[5, 6] Although the hepatoprotective function of IL-6 has been well documented, clinical application of IL-6 for ALD treatment is limited by the many potential side effects of Selleck Cyclopamine IL-6, which likely result from the ubiquitous expression of IL-6 receptor. This led us to explore another hepatoprotective cytokine IL-22, which activates similar signaling selleck chemicals llc pathways (such as STAT3) as those activated by IL-6 in hepatocytes.

Importantly, IL-22 receptor expression is restricted to epithelial cells, which suggests that IL-22 treatment would likely produce fewer side effects than IL-6, and is an attractive candidate for ALD therapy. Initially identified as a gene induced by IL-9 in mouse T lymphocytes, IL-22 shares 22% amino acid identity with IL-10 and belongs to IL-10 family.[7] Both IL-10 and IL-22 utilize the ubiquitously expressed IL-10R2, but IL-10 signaling also requires IL-10R1, which is expressed on immune cells, whereas IL-22 signaling needs IL-22R1, which is expressed on epithelial cells.[8] Thus, IL-10 targets immune cells and acts as an important anti-inflammatory cytokine; IL-22 targets epithelial cells and plays an important role in promoting tissue repair. After binding to IL-22R1 and IL-10R2, IL-22 predominantly induces STAT3 activation, and to a lesser extent, activation of other signaling pathways such as STAT1, STAT5, mitogen-activated protein kinases in epithelial cells, followed by upregulating expression of many genes that control anti-microbial immunity and tissue repair.