Background/Aim: Interleukin 22 (IL-22) is a Th17 cell hepatoprotective cytokine that is undergoing clinical trials to treat patients with alcoholic hepatitis (AH). Lipopolysaccharide (LPS) activation of macrophage is implicated in hepatocyte cell death and pathogenesis of AH. The role of IL-22 production from macrophage, its regulation by LPS and effects on alcohol induced hepatocyte cell death are unexplored and were examined in this study. Methods/Results: Low levels of IL-22 mRNA/protein were detected in macrophage but were significantly upregulated by 6.5 fold in response to the tissue reparative cytokine IL-10. Conversely, LPS significantly decreased IL-22 mRNA levels in a temporal and concentration dependent manner with a maximum reduction of 5-fold. Since LPS downregulation of IL-22 mRNA levels was rescued in the presence of a pharmacologic inhibitor of c-jun N-terminal kinase (JNK) and by JNK knockdown. Next, we explored if macrophage-derived IL-22 regulated ethanol induced hepatocyte death. Conditioned media from IL-10 stimulated macrophage attenuated ethanol induced hepatocyte caspase-3/7 activity and apoptosis as assessed by fluorimetric assay and TUNEL staining, respectively. This effect was diminished in conditioned media from macrophages with IL-22 knockdown. Cytokine analysis in sera samples of patients with AH revealed that IL-22 levels were significantly elevated compared with healthy controls and heavy drinking controls implying a state of IL-22 resistance in human AH. Conclusions: Macrophage-derived IL-22 protects hepatocytes from ethanol induced cell death. IL-22 downregulation is a new regulatory target of LPS in the pathogenesis of AH. -