Involvement of the CXCL12/CXCR4 pathway in the advanced liver disease that is associated with hepatitis C virus or hepatitis B virus

Ori Wald, Orit Pappo, Rifaat Safadi, Michal Dagan-Berger, Katia Beider, Hanna Wald, Suzanna Franitza, Ido Weiss, Shani Avniel, Pal Boaz, Jacob Hanna, Gidi Zamir, Ahmed Eid, Ofer Mandelboim, Ulrich Spengler, Eithan Galun, Amnon Peled*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

Abstract

Chronic hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is accompanied by inflammation and fibrosis eventually leading to cirrhosis. The chemokine CXCL12 is involved in chronic inflammatory conditions. The role of the CXCL12/CXCR4 pathway in HCV- and HBV-associated liver inflammation and fibrosis was therefore studied. The levels and tissue localization of CXCL12 in liver and plasma of HCV and HBV patients were tested using immunohistochemistry and ELISA. The expression and function of CXCR4 on liver-infiltrating lymphocytes (LIL) were tested by FACS and transwell migration assays. We found that CXCL12 is expressed by bile duct epithelial cells in normal liver tissue. Bile duct proliferation and liver fibrosis in chronic HCV and HBV infection result in the anatomical re-distribution of CXCL12 in the liver. Moreover, CXCL12 is up-regulated in the endothelium of neo-blood-vessels formed in active inflammatory foci and is significantly elevated, compared with controls, in the plasma of patients with advanced liver fibrosis. Complementing these observations were others indicating that over 50% of LIL express CXCR4 and, in response to CXCL12, migrated and adhered to fibronectin. These observations suggest an important role for the CXCL12/CXCR4 pathway in recruitment and retention of immune cells in the liver during chronic HCV and HBV infection.

Original languageAmerican English
Pages (from-to)1164-1174
Number of pages11
JournalEuropean Journal of Immunology
Volume34
Issue number4
DOIs
StatePublished - Apr 2004
Externally publishedYes

Keywords

  • CXCR4
  • Chemokine
  • Cirrhosis
  • Fibrosis
  • Inflammation

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