Wald Ori, Pappo Orit, Safadi Rifaat, Dagan-Berger Michal, Beider Katia, Wald Hanna, Franitza Suzanna, Weiss Ido, Avniel Shani, Boaz Pal, Hanna Jacob, Zamir Gidi, Eid Ahmed, Mandelboim Ofer, Spengler Ulrich, Galun Eithan, Peled Amnon
Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel.
Eur J Immunol. 2004 Apr;34(4):1164-74. doi: 10.1002/eji.200324441.
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.
慢性丙型肝炎病毒（HCV）和乙型肝炎病毒（HBV）感染会伴随炎症和纤维化，最终导致肝硬化。趋化因子CXCL12参与慢性炎症状态。因此，研究了CXCL12/CXCR4通路在HCV和HBV相关的肝脏炎症及纤维化中的作用。采用免疫组织化学和酶联免疫吸附测定法检测HCV和HBV患者肝脏及血浆中CXCL12的水平和组织定位。通过荧光激活细胞分选术（FACS）和Transwell迁移试验检测肝脏浸润淋巴细胞（LIL）上CXCR4的表达和功能。我们发现，正常肝组织中的胆管上皮细胞表达CXCL12。慢性HCV和HBV感染中的胆管增生和肝纤维化导致肝脏中CXCL12的解剖学重新分布。此外，CXCL12在活跃炎症灶中形成的新生血管内皮中上调，与对照组相比，晚期肝纤维化患者血浆中的CXCL12显著升高。补充这些观察结果的还有其他发现，即超过50%的LIL表达CXCR4，并且在对CXCL12产生反应时，迁移并黏附于纤连蛋白。这些观察结果表明，CXCL12/CXCR4通路在慢性HCV和HBV感染期间肝脏中免疫细胞的募集和滞留中发挥重要作用。
