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

Abstract

Fractalkine is a chemokine with both chemoattractant and cell-adhesive functions, and in the intestine it is involved with its receptor CX3CR1 in the chemoattraction and recruitment of intraepithelial lymphocytes. We examined the pathophysiological roles of fractalkine and CX3CR1 in normal and diseased bile ducts. Expression of fractalkine and CX3CR1 were examined in liver tissues from patients with primary biliary cirrhosis (17 cases) and controls (9 cases of primary sclerosing cholangitis, 10 cases of extrahepatic biliary obstruction, 20 cases of chronic viral hepatitis C, and 18 cases of histologically normal livers). Expression of fractalkine in biliary epithelial cells (BECs) in response to cytokine treatments was examined using a human cholangiocarcinoma cell line (HuCC-T1) and human intrahepatic BEC line. The chemotaxis of CX3CR1-expressing monocytes (THP-1) toward fractalkine was assayed using chemotaxis chambers. Fractalkine messenger RNA/protein were expressed on BECs of normal and diseased bile ducts, and their expression was upregulated in injured bile ducts of primary biliary cirrhosis. CX3CR1 was expressed on infiltrating mononuclear cells in portal tracts and on CD3

Clinicopathological Significance of Serum Fractalkine in Primary Biliary Cirrhosis

“…This trend confirmed the findings in our previous report [9], where serum fractalkine levels in all controls including healthy controls and patients with extrahepatic biliary obstruction and HCV-related chronic hepatitis were <3.0 ng/ml [9]. Next, the correlation between fractalkine levels and liver function data (ALT and ALP levels) and IgM levels was examined.…”

“…We previously reported that damaged bile ducts and vessels in PBC express fractalkine and that the induction of fractalkine expression in biliary epithelial cells is closely associated with biliary and periductal innate immunity [9,10]. In the present study, we measured serum fractalkine levels using different PBC patients' sera and obtained a similar average and distribution.…”

“…Most cases had levels <3 ng/ml, but 14 patients had high levels (>5 ng/ml). These high levels were only observed in PBC patients; levels in the healthy population and patients with other liver diseases were <3 ng/ml [9]. Therefore, in PBC patients with high fractalkine levels, intrahepatic fractalkine produced by liver constituent cells, including biliary epithelial cells, is the likely cause of the increase in serum fractalkine.…”

“…UDCA is a hydrophilic, nontoxic bile acid that contributes nearly 3% to the normal bile acid pool in humans and has cytoprotective, anti-apoptotic, membrane stabilizing, antioxidative, and immunomodulatory effects [19]. In our previous study, we demonstrated that upregulation of fractalkine expression in biliary epithelial cells is induced by the biliary innate immune response [9]. Therefore, it is possible that UDCA directly regulates the production of fractalkine in liver constituent cells, including biliary epithelial cells, but further study is needed to clarify the direct correlation between the effectiveness of UDCA and serum fractalkine levels.…”

“…We previously reported that the level of fractalkine is significantly elevated in the sera of PBC patients and in small bile ducts, particularly those that are damaged. In addition, vascular endothelial cells expressing fractalkine is increased in PBC [9], suggesting that fractalkine is an important mediator associated with the continuous portal, particularly periductal, inflammation of PBC. Moreover, the expression of fractalkine in bile ducts is reported to be associated with innate immunity via Toll-like receptor (TLR) 3 and TLR4 in vascular endothelial cells, infiltrating mononuclear cells, and biliary epithelial Harada -4 -cells [10,11].…”