Hepatic expression of CCL2 in alcoholic liver disease is associated with disease severity and neutrophil infiltrates

Abstract

SummarySerum levels and liver expression of CCL2 are increased in patients with alcoholic hepatitis (AH). In an experimental model of alcoholic liver disease (ALD), CCL2 was implicated in proinflammatory cytokines activation and hepatic lipid metabolism, but its role in human disease is currently unknown. In a large cohort of ALD patients, we analysed plasma levels and liver expression of CCL2 and their association with liver disease severity and histological lesions. We also studied the relationship between -2518 A > G CCL2 and CCR2 190 A/G polymorphisms and severity of ALD. We show that CCL2 plasma levels are increased in ALD patients compared with healthy subjects. AH patients had significantly higher plasma levels and hepatic expression of CCL2 than patients without AH. Plasma levels and hepatic expression of CCL2 were associated with disease severity. CCL2 liver expression was correlated with neutrophil infiltrate and interleukin (IL)-8 expression, but not with steatosis. Moreover, there were more G-allele carriers of -2518 A > G CCL2 polymorphism in severe AH patients than in other ALD patients. Our results demonstrate that CCL2 is increased in ALD, particularly in severe forms, and suggest a role for CCL2 in the pathogenesis of ALD via neutrophil recruitment.

EGCG attenuates pro-inflammatory cytokines and chemokines production in LPS-stimulated L02 hepatocyte

“…Besides, significant increases of the levels of Rantes, TNF-a, and NO in Hepatitis C virus-infected patients are observed [19]. Another study has shown that MCP-1 plasma levels are higher in both alcoholic liver disease and alcoholic hepatitis patients than in the controls, and alcoholic hepatitis patients have significantly higher hepatic expression of MCP-1 [20]. Our results indicated that EGCG inhibited the expression of Rantes and MCP-1, which in turn inhibited the migration of inflammatory cells into the liver, thus reducing liver injury severity.…”

Roles for Chemokines in Liver Disease

“…102 Among CC chemokines, CCL2 has recently been suggested to play a role in alcohol-related damage, because its liver and plasma levels were associated with disease severity and with inflammation, including neutrophil infiltration, but not with steatosis, in patients with alcoholic liver disease. 103 Interestingly, polymorphisms in the CCL2 and CCR2 genes were more frequent in patients with severe disease. These lines of evidence are supported by experimental findings in mice deficient in CCL2 fed a Lieber-DeCarli diet for 6 weeks.…”

The role of neutrophils in the development of liver diseases

“…Expression levels of CCL2 in the serum and liver was increased in alcoholic hepatitis patients, and this increase was pronounced in severe forms of the disease. 39 Furthermore, Ziol and colleagues 40 analyzed 35 alcoholic hepatitis patients and found that the hepatocyte apoptotic index, but not the ballooning hepatocyte index, was strongly correlated with the neutrophil infiltration index. Therefore, understanding of the role of the innate immune system, particularly the role of neutrophils, in alcoholic liver disease pathogenesis may help to identify novel therapeutic targets for this disease.…”