Monocyte chemotactic protein-1, -2, and -3 are distinctively expressed in portal tracts and granulomata in primary biliary cirrhosis: implications for pathogenesis

Abstract

The monocyte chemotactic proteins (MCPs) form a distinct structurally related subclass of C±C chemokines. MCPs select speci®c target cells due to binding to a distinct set of chemokine receptors and because of their effects on monocytes, and may participate in the process of granuloma formation during bacterial and/or mycobacterial infections. The aetiology of primary biliary cirrhosis (PBC) is still unclear, although bacterial infection and autoimmune processes have been implicated. In this study, the expression of three of the most potent monocyte chemoattractants, MCP-1, -2, and -3, was examined in patients with PBC and the data were compared with results for other liver diseases including primary sclerosing cholangitis (PSC), chronic viral hepatitis C, hepatic sarcoidosis, and normal liver. MCP-1 was expressed mainly in biliary epithelial cells of all liver specimens, irrespective of the cause of disease. Some mononuclear leukocytes in the portal tract expressed MCP-1 in all the disease groups examined and there were no signi®cant differences in frequency between these groups. In contrast, more than 80% of PBC livers showed MCP-2-and MCP-3-positive mononuclear leukocyte in®ltration in portal tracts, particularly around the bile ducts, whereas such cells were far less frequent in the other disease groups or in normal livers. Epithelioid granulomata of PBC patients contained MCP-2-and MCP-3-positive cells at their edge. In double staining experiments, more than 60% of the MCP-positive mononuclear cells co-expressed CD68, suggesting that a proportion of MCP-2-and MCP-3-positive cells are derived from monocytes. These monocytes expressing MCP-2 and MCP-3 may be responsible for the chemotactic activity of more monocytes. Such an expression pattern of MCP-1, -2 and -3 in portal tracts seems to be distinctive for PBC. This pattern underlines the importance of MCP-1, -2, and -3 in the recruitment of monocytes and possibly T lymphocytes into portal tracts, around the injured bile ducts, and into epithelioid granulomata in PBC. The data further implicate bacterial materials derived from bile in the overall pathogenesis of PBC.

Fibrogenesis in pediatric cholestatic liver disease: Role of taurocholate and hepatocyte-derived monocyte chemotaxis protein-1 in hepatic stellate cell recruitment

“…26,27 The finding of MCP-1 expression in hepatocytes, particularly those at the edge of active fibrosis, is novel and may be unique to cholestatic liver diseases such as BA and CFLD, because previous studies in adult chronic viral hepatitis have reported expression of MCP-1 limited to inflammatory cells, cholangiocytes, and HSCs. Chemokines generally regulate leukocyte recruitment to various tissues of the body, including the liver.…”

Armed CD4+ Th1 effector cells and activated macrophages participate in bile duct injury in murine biliary atresia

“…Cameron et al reported persistent activation of macrophages in livers of patients with primary sclerosing cholangitis, which participate in the chronic release of TGF-γ and contribute to the chronic inflammation and fibrosis [27]. Primary biliary cirrhosis is associated with Kupffer cell portal tract infiltrates that express monocyte chemotactic proteins, resulting in persistent recruitment of monocytes surrounding bile ducts [28].…”

Fractalkine and CX3CR1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts

“…8 Biliary epithelial cells (BECs) are known as immunologically potent cells, and BECs of inflamed bile ducts actively participate in inflammation by secreting cytokines and expressing immune receptors. 9,10 Chemokines also are expressed on pathological bile ducts. 10,11 For ex-ample, Terada et al 12 reported that stromal-derived factor 1 expressed on bile ducts is responsible for the migration and recruitment of lymphoid cells in portal tracts and around bile ducts in primary biliary cirrhosis (PBC) as well as in chronic viral hepatitis (CVH).…”

“…9,10 Chemokines also are expressed on pathological bile ducts. 10,11 For ex-ample, Terada et al 12 reported that stromal-derived factor 1 expressed on bile ducts is responsible for the migration and recruitment of lymphoid cells in portal tracts and around bile ducts in primary biliary cirrhosis (PBC) as well as in chronic viral hepatitis (CVH). Although the upregulation of fractalkine and CX3CR1 expression has been reported in hepatic parenchyma and bile ductules of hepatitis C virus-infected livers, 13 their expression and immunopathological significance remain unexplored in normal and pathological bile ducts.…”