001), whereas differences between early (Child A) and decompensated (Child C) cirrhosis did not reach statistical significance (Fig. 1A). The underlying disease etiology did not influence ATM inhibitor the serum fractalkine level (Fig. 1B). Moreover, the serum fractalkine level correlated with clinical scores of disease progression [r = 0.236 and P = 0.021 for Child-Pugh points and r = 0.336 and P = 0.001 for Model for End-Stage Liver Disease (MELD) scores; Fig. 1C], correlated inversely with liver function (e.g., r = −0.296 and P < 0.001 for albumin, r = 0.365 and P < 0.001 for bilirubin, r = −0.364 and P < 0.001 for cholinesterase, and r = 0.236 and P = 0.002 for the international normalized ratio), and correlated

with noninvasive quantitative selleck products fibrosis markers (r = 0.388 and P < 0.001 for hyaluronic acid and r = 0.465 and P < 0.001 for

procollagen III peptide; Fig. 1C). We next assessed the intrahepatic gene expression of CX3CL1 and CX3CR1 in patients with different stages of fibrosis by real-time qPCR. The intrahepatic expression of cx3cl1 was down-regulated when we compared nonfibrotic or fibrotic livers with cirrhotic livers (Fig. 1D). Intrahepatic cx3cr1 expression was strongly reduced in cirrhotic livers versus fibrotic or nonfibrotic livers (Fig. 1D). This finding was in sharp contrast to the increased numbers of macrophages that were observed in cirrhotic livers,17 and this suggested that the down-regulation of CX3CR1 in the cirrhotic liver (not a lack of CX3CR1-expressing

cells) was responsible for this finding. Collectively, these data demonstrate that progressive liver fibrosis in humans is associated with an increase in circulating fractalkine and a reduction of intrahepatic CX3CR1 expression. In order to address the functional role of CX3CR1 in hepatic injury and fibrogenesis, WT and CX3CR1-deficient mice were subjected to CCl4-induced liver injury. After a single injection of CCl4 and selleck compound during chronic liver injury induced by twice weekly CCl4 injections for 6 weeks, fractalkine gene expression was significantly up-regulated in the livers of WT and CX3CR1−/− mice (Supporting Fig. 1 and data not shown). At 24 and 48 hours after a single intraperitoneal administration of CCl4, WT and CX3CR1-deficient mice displayed massive hepatocyte necrosis and high ALT levels (Fig. 2A,B). However, CX3CR1−/− mice showed prolonged histological signs of injury and significantly elevated ALT levels at 72 and 120 hours (Fig. 2A,B), whereas WT animals fully recovered within 5 days after CCl4, as anticipated from previous studies.5 We next analyzed leukocyte infiltration into livers after CCl4-induced injury by FACS. In line with prolonged liver damage, CX3CR1−/− mice displayed a prolonged elevation of intrahepatic leukocytes at 72 and 120 hours, whereas intrahepatic leukocyte counts were almost normalized in WT mice at 120 hours after CCl4 treatment (Fig. 2C).