5A,B). These results indicate not only that a GAS6 deficiency sensitizes mice to I/R-induced liver damage but also that the elevation of serum GAS6 levels is a protective strategy against liver I/R injury. Our findings have disclosed a novel role for GAS6 in hepatocellular defense against hypoxia and I/R and have expanded our knowledge of the biological

facets of this atypical member of the vitamin K–dependent family, which has negligible anticoagulant function but is recognized to be involved in cancer, inflammation, and the regulation of liver regeneration and fibrosis.1, 2, 5, 6 Specifically, we have shown that GAS6 is dispensable for the activation of JNK and NF-κB during hepatic I/R but is required for efficient AKT phosphorylation in hepatocytes; this agrees with previous findings reported for other cell types.3 In addition to increased susceptibility to

hepatic I/R injury, GAS6-null mice exhibit enhanced BGB324 research buy expression of IL-1β and TNF, and this suggests that GAS6 may mediate the suppression of liver inflammation during I/R. These findings are in line with previously reported data on human Idasanutlin research buy and murine monocytes/macrophages20, 21, 32 and Sertoli cells30 via the regulation of TAM receptor signaling.1 Together, our findings indicate that the susceptibility to hepatic I/R injury in the absence of GAS6 reflects the combination of the inability to turn on survival pathways dependent on AKT activation and the overstimulation of inflammatory cytokines. Interestingly, this hepatoprotective role displayed by GAS6 against I/R contrasts

with findings in mouse hearts subjected to warm ischemia, in which GAS6 promoted graft destruction by enhancing interactions between endothelial cells, platelets, and leukocytes33; this exemplifies the importance of organ-dependent mechanisms in GAS6 signaling. The outcome of GAS6-null mice after hepatic I/R is reversible upon the addition of GAS6, and this suggests the maintenance of TAM receptors in the null mice and the functional interaction of GAS6 with TAM receptors. Among TAM receptors, most of the protective effects of GAS6 described in different cell types are due to the binding of GAS6 to Axl.34-37 In 上海皓元 contrast to these findings, Axl seems to play a minor role in hepatic I/R because increased Axl phosphorylation was not detected after I/R exposure. Instead, Mer becomes phosphorylated in WT mice after I/R, and this response is blunted in GAS6-KO mice. Moreover, recent data on differentiated monocytes and macrophages have shown that GAS6 inhibits TNF and IL-1β stimulation in response to LPS via Mer activation.21 Moreover, the binding of GAS6 to Mer but not to Axl or Tyro3 results in the activation of AKT via glycogen synthase kinase 3β phosphorylation, which in turn prevents NF-κB activation. Together, these data and the present study expand our knowledge of the biological impact of the GAS6-Mer interaction, which elicits a combined anti-inflammatory and survival pathway to protect against hepatic I/R.