8C). This may help explain a lack of correlation between inflammation and hepatocellular damage (serum ALT levels) observed in some patients with chronic liver diseases.8-13 In our study, injection with CCl4 induced much higher levels of systemic and hepatic inflammation in STAT3 mice than in wild-type mice, suggesting that STAT3 in myeloid cells plays an important role in inhibiting inflammation in a

model of CCl4-induced liver injury. This is consistent with previously well-documented studies showing the anti-inflammatory effects of STAT3 in 5-Fluoracil datasheet myeloid cells using various models of organ injury.26-28 Surprisingly, despite higher levels of inflammation in STAT3 mice, they had much lower serum ALT levels and less liver necrosis than wild-type mice after CCl4 administration.

The resistance of STAT3 mice to CCl4-induced liver necrosis may be attributable to either the impaired ability of STAT3-deficient neutrophils/macrophages to induce hepatocellular damage or the resistance of hepatocytes to CCl4-induced hepatocellular damage in STAT3 mice. Several lines of evidence suggest that it is the second mechanism that contributes to reducing liver necrosis in STAT3 mice because of enhanced STAT3 activation in the liver. The hepatotoxicity of CCl4 is mediated by the direct induction of hepatocyte damage U0126 in vivo and indirect activation of Kupffer cells/macrophages and neutrophils.14 Activated Kupffer cells/macrophages produce free radicals and proinflammatory cytokines such as TNF-α that further trigger hepatocellular damage and induce neutrophil accumulation and activation.2, 5 Activated neutrophils can cause hepatocyte damage by releasing oxygen species and proteases.2, 5 We have

previously shown that Kupffer cells from STAT3 mice produce much higher levels of reactive oxygen species and TNF-α compared with those from wild-type mice.27 By using four different assays, Lee et al.29 previously demonstrated that STAT3-deficient neutrophils mature normally and are functional. In the 上海皓元 current study we also confirmed that STAT3-deficient neutrophils from STAT3 mice are functional in vitro because they produced a similar respiratory burst after phorbol 12-myristate 13-acetate stimulation compared with phorbol 12-myristate 13-acetate–stimulated wild-type mouse neutrophils (Supporting Fig. S1c). Moreover, an additional deletion of STAT3 in hepatocytes restored liver necrosis in STAT3 mice after CCl4 administration, suggesting that neutrophils from STAT3 mice are functional in vivo. Collectively, these findings suggest that STAT3-deficient macrophages and neutrophils in STAT3 mice have normal ability to induce inflammatory responses and hepatocellular damage, and that the reduced liver necrosis observed in STAT3 mice is not attributable to a defect in STAT3-deficient macrophages and neutrophils to induce hepatocellular damage.