Stromal Cell–Derived Factor-1 from Biliary Epithelial Cells Recruits CXCR4-Positive Cells: Implications for Inflammatory Liver Diseases

Abstract

SUMMARY:Although stromal cell-derived factor-1 (SDF-1) plays an important role in hematopoiesis in the fetal liver, the role after birth remains to be clarified. We investigated the role of SDF-1 and its receptor, CXCR4, in 75 patients; this included controls and patients with viral hepatitis, liver cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. Interestingly, SDF-1 appeared up-regulated in biliary epithelial cells (BEC) of inflammatory liver disease. Furthermore, in inflammatory liver diseases, SDF-1 was expressed by BEC of interlobular and septal bile ducts and by proliferated bile ductules. The message expression of SDF-1 in BEC was confirmed at a single-cell level by RT-PCR and laser capture microdissection. The plasma levels of SDF-1 were significantly higher in patients with liver diseases than in normal controls. Flow cytometric analysis of the surface expression of CXCR4 showed that most liver-infiltrating lymphocytes express CXCR4 and the intensity was up-regulated more significantly in liver-infiltrating lymphocytes than in peripheral blood lymphocytes. These results suggest that increased SDF-1 production by BEC may play an important role in the recruitment of CXCR4-positive inflammatory cells into the diseased livers. These data are significant because modulation of the SDF-1/CXCR4 interaction has therapeutic implications for inflammatory liver diseases. (Lab Invest 2003, 83:665-672).

Expression of Stromal Cell-Derived Factor-1 and of Its Receptor CXCR4 in Liver Regeneration from Oval Cells in Rat

“…We demonstrate that oval cells synthesize SDF-1, as shown by in situ hybridization and by immunohistochemistry. Stromal cell-derived factor-1 immunolabeling has already been demonstrated in cholangiolar cells in a variety of human chronic liver diseases 28 and in biliary ductal plate epithelial cells during development. 22 However, in the latter study, it was not clear whether SDF-1 was synthesized by labeled cells or if it was of exogenous origin and bound to cell surface receptors or to plasma membrane-associated heparan sulfates.…”

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

“…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.…”

Biliary Epithelial Cells Are Not the Predominant Source of Hepatic CXCL12

“…5 Finally, with injury, immunohistochemical data demonstrate robust CXCL12 expression by proliferating bile ductules in all forms of liver injury, and biliary CXCL12 expression is further supported by the accumulation of CXCR4-positive lymphocytes in the periportal region. 2,6 A careful review of the literature, however, reveals that most data supporting BEC expression of CXCL12 are based on immunohistochemistry using a single monoclonal CXCL12 antibody (murine anti-human/mouse CXCL12, clone 79018). We believe that differentiated BECs may not express CXCL12 and that the observed pattern of BEC expression is a result of antibody crossreactivity to an epitope found in BECs.…”

“…Herein, we show that despite previous studies demonstrating robust CXCL12 expression by BECs, their role in hepatic CXCL12 production may be more limited. 2,6,8 …”