The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection.

Abstract

BACKGROUND/AIMS:

The chemokine receptor CX3CR1 and its specific ligand fractalkine (CX3CL1) are known to modulate inflammatory and fibroproliferative diseases. Here we investigate the role of CX3CR1/fractalkine in HCV-induced liver fibrosis.

METHODS:

A genotype analysis of CX3CR1 variants was performed in 211 HCV-infected patients. Hepatic expression of CX3CR1 was studied in HCV-infected livers and isolated liver cell populations by RT-PCR and immunohistochemistry. The effects of fractalkine on mRNA expression of profibrogenic genes were determined in isolated hepatic stellate cells (HSC) and CX3CR1 genotypes were related to intrahepatic TIMP-1 mRNA levels.

RESULTS:

The intrahepatic mRNA expression of CX3CR1 correlates with the stage of HCV-induced liver fibrosis (P=0.03). The CX3CR1 coding variant V249I is associated with advanced liver fibrosis, independent of the T280M variant (P=0.009). CX3CR1 is present on primary HSC and fractalkine leads to a suppression of tissue inhibitor of metalloproteinase (TIMP)-1 mRNA in HSC (P=0.03). Furthermore, CX3CR1 genotypes are associated with TIMP-1 mRNA expression in HCV-infected liver (P=0.03).

CONCLUSIONS:

The results identify the fractalkine receptor CX3CR1 as susceptibility a gene for hepatic fibrosis in HCV infection. The modulation of TIMP-1 expression by fractalkine and CX3CR1 genotypes provides functional support for the observed genotype-phenotype association.

• Authors: Hermann E Wasmuth, Mirko Moreno Zaldivar, Marie-Luise Berres, Alexa Werth, David Scholten, Sonja Hillebrandt, Frank Tacke, Petra Schmitz, Edgar Dahl, Tonio Wiederholt, Claus Hellerbrand, Thomas Berg, Ralf Weiskirchen, Christian Trautwein, Frank Lammert
• Journal: Journal of hepatology (J Hepatol) Vol. 48 Issue 2 Pg. 208-15 (Feb 2008) ISSN: 0168-8278 [Print] Netherlands
• PMID: 18078680 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CX3C Chemokine Receptor 1
• CX3CR1 protein, human
• RNA, Messenger
• Receptors, Chemokine
• Tissue Inhibitor of Metalloproteinase-1

Topics

• CX3C Chemokine Receptor 1
• Genotype
• Hepatitis C, Chronic (complications, genetics)
• Humans
• Liver (metabolism)
• Liver Cirrhosis (etiology, genetics)
• Polymorphism, Single Nucleotide
• RNA, Messenger (analysis)
• Receptors, Chemokine (genetics)
• Tissue Inhibitor of Metalloproteinase-1 (genetics)