These cells could, in turn, recruit neutrophils. Because livers of ALD patients, particularly those with AH, are infiltrated by IL-17+ cells [20], and because Th-17 cells play a role in neutrophil recruitment and express

CCR2 [22], we correlated CCL2 liver expression with IL-17+ cell infiltrates. We found that CCL2 liver expression was correlated with numbers of IL-17+ cells. Furthermore, IL-17+ cell infiltrates were correlated strongly with neutrophil infiltrates and with IL-8 liver expression. These results suggest that CCL2 plays a role in the pathogenesis of ALD by recruitment of Th17 cells which, in turn, would recruit neutrophils via an IL-8 effect. C646 However, IL-17+ cell infiltrates may, in part, reflect neutrophil infiltrates. Indeed, we have shown previously, using confocal microscopy, that among liver-infiltrating IL-17+, T lymphocytes and neutrophils were represented most frequently [20]. As each AH episode is thought to be profibrogenic [4], we speculate that CCL2 secreted during the AH inflammatory burden

could enhance the fibrogenesis process. However, we found no difference in liver CCL2 expression between ALD patients with and without cirrhosis; nevertheless, this result should be viewed with caution, as non-cirrhotic patients in our cohort were scarce. We found no correlation between CCL2 liver expression and hepatic steatosis in our patient cohort, whereas CCL2 was involved in hepatic lipid metabolism in an experimental model of alcoholic liver disease high throughput screening [16]. This relationship between CCL2 liver expression and steatosis may be present in the beginning of ALD, mTOR inhibitor but not in severe disease such as cirrhosis. Patients with the G-allele for −2518 A > G CCL2 polymorphism were present more frequently in the severely ill AH group than in other ALD patients. Moreover, among AH patients, the G-allele was more frequent in the severe form of the disease. It was shown previously

that the presence of the −2518 G-allele resulted in significantly greater CCL2 secretion than that found in patients with the A/A homozygous genotype in response to a given inflammatory stimulus [23], and this polymorphism has been implicated in numerous inflammatory diseases, including hepatitis C, acute pancreatitis, Crohn’s disease and, more recently, spontaneous bacterial peritonitis [24,25,28,29]. However, we did not find higher CCL2 plasma levels or liver expression in G-allele carriers in our cohort of patients (data not shown). It is possible that G-allele carriers are more likely to develop a severe form of AH, but that the levels of CCL2 at the time of alcoholic hepatitis are the same as in G-non-carriers. Our finding suggests that G-allele carriers are more likely to develop a severe form of AH than patients without the G-allele when exposed to alcohol.