All STAT3Mye−/−STAT1−/− mice survived after PHx (data not shown) and had comparable liver regeneration as STAT3Mye−/− mice (Fig. 6B). Infiltration of neutrophils and macrophages was reduced in STAT3Mye−/− STAT1−/− mice compared with STAT3Mye−/− mice (data not shown). Elevation of serum inflammatory cytokines was also diminished in the former relative to the click here latter group (Fig. 6C). Western blotting (Fig. 7 A) confirmed the absence of STAT1 protein expression in hepatocytes and liver leukocytes, and the absence of STAT3 protein expression in hepatocytes and its very low level in liver leukocytes in STAT3Mye−/−Hep−/−STAT1−/−

triple KO mice. All STAT3Mye−/−Hep−/−STAT1−/− triple KO mice survived after PHx, in contrast to the 25% survival this website of STAT3Mye−/−Hep−/− mice (Fig. 7B). Furthermore, the STAT3Mye−/−Hep−/−STAT1−/− mice had enhanced liver regeneration, reduced hepatocyte apoptosis, and reduced serum cytokines

after PHx compared to STAT3Mye−/−Hep−/− mice (Fig. 7C,D). These findings suggest that deletion of STAT1 rescues liver function and regeneration, and attenuates the innate inflammatory response as compared to STAT3Mye−/−Hep−/− double KO mice. In this article, we demonstrate for the first time that PHx results in STAT3 activation in immune cells, in addition to its activation in the liver, as reported previously.8 Additionally, our results indicate that activation of STAT3 in myeloid lineage cells and hepatocytes act in concert to effectively temper the systemic and hepatic inflammatory responses, ensuring normal liver regeneration, as summarized in a proposed model in Fig. 8. The rationale for this model is presented below. STAT3 is activated in both the liver and myeloid cells after PHx

(Fig. 1). Elevation of IL-6 is likely responsible for STAT3 activation in the liver because such activation is markedly diminished in IL-6 KO mice.8, 11 At present, the mechanisms underlying PHx-induced STAT3 activation in myeloid cells are not clear. Both IL-6 and IL-10 are known to activate STAT3 in myeloid cells and to be elevated in the liver and serum after PHx.8, 22 Thus, both of these cytokines likely contribute to STAT3 activation in myeloid cells. Deletion of STAT3 in myeloid cells resulted in increased infiltration of macrophages and medchemexpress neutrophils into the remnant liver following PHx. Production of the proinflammatory cytokines TNF-α and IL-6 by these cells leads to activation of STAT3 in the liver. This may be responsible for the enhanced liver regeneration observed in STAT3Mye−/− mice after PHx (Fig. 2), because all of these factors have been shown to promote liver regeneration.8, 23, 24 Deletion of STAT3 in myeloid cells also resulted in elevated serum levels of IFN-γ, a cytokine known to induce hepatocyte apoptosis and cell cycle arrest via activation of the STAT1 signaling pathway.21 However, despite the high serum levels of IFN-γ, activation of STAT1 was not detected in the liver of STAT3Mye−/− mice after PHx (Fig. 4A).