20 reported that injection of 5 × 1010 particles of IL-22 adenovirus resulted

in serum levels of 35,000-95,000 pg/mL IL-22 and causes hematological changes, loss of body weight, PLX4032 price and thymic atrophy, whereas we have previously shown that injection of 2 × 108 particles of IL-22 adenovirus resulted in serum levels of 5,000 pg/mL IL-22 (similar to those in liver-specific IL-22TG mice) and did not induce obvious adverse phenotypes.14 These findings suggest that only very high doses of IL-22 may cause severe adverse phenotypes. However, it is unlikely that therapeutic application of IL-22 will reach such high concentrations of IL-22 (35,000-95,000 pg/mL) in the serum reported in the study by Liang et al.20 Regardless, monitoring IL-22 levels will be important in any therapeutic applications. Although the hepatoprotection of IL-22 is well documented,12-14 the role of IL-22 in liver inflammation remains obscure. Liang et al20 reported that a single injection of IL-22 up-regulated expression of CXCL1 in the liver, followed by a transient increase in circulating neutrophils, X-396 ic50 suggesting IL-22 may promote liver inflammation. In contrast, blockage of IL-22

either through using a neutralizing antibody12 or genetic deletion13 exacerbated inflammation, whereas treatment with IL-2212 or overexpression of IL-22 (the current study) ameliorated ConA-induced liver inflammation, indicating IL-22 suppresses liver inflammation in this model. It is plausible that IL-22 plays dual roles in controlling liver inflammation: promoting liver inflammation by stimulating hepatocytes to produce

acute phase proteins and chemokines, and inhibiting liver inflammation by preventing hepatocyte damage and subsequently reducing necrosis-associated liver inflammation. The final effect of IL-22 on liver inflammation is likely determined by the balance between the proinflammatory and anti-inflammatory effects of IL-22 and is dependent on the types of liver diseases and liver injury models. A previous study reported that the expression of hepatic IL-22 messenger RNA was up-regulated in patients with viral hepatitis.23 Here we demonstrate that IL-22+ immune cells are accumulated in the livers of patients with viral hepatitis (Fig. 1); however, the types of inflammatory Dehydratase cells responsible for IL-22 production in viral hepatitis patients remain obscure. Because Th17, Th22, natural killer, and natural killer T cells, which are known to produce IL-22,2-4 are elevated in the livers in patients with viral hepatitis,24-26 these cells likely contribute to hepatic IL-22 expression in the patients. Further studies are needed to confirm this assessment. The next obvious question is how IL-22 up-regulation might affect the progression of viral hepatitis disease progression. First, it has been reported that IL-22 does not inhibit HCV replication in vitro,23 suggesting that elevated IL-22 may not affect HCV replication directly.