The fractalkine receptor CX3CR1 is involved in liver fibrosis due to chronic hepatitis C infection.
OBJECTIVE
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.
Wasmuth
Hermann E
HE
Medical Department III, University Hospital Aachen, Pauwelsstrasse 30, D-52057 Aachen, Germany. hwasmuth@ukaachen.de
Zaldivar
Mirko Moreno
MM
Berres
Marie-Luise
ML
Werth
Alexa
A
Scholten
David
D
Hillebrandt
Sonja
S
Tacke
Frank
F
Schmitz
Petra
P
Dahl
Edgar
E
Wiederholt
Tonio
T
Hellerbrand
Claus
C
Berg
Thomas
T
Weiskirchen
Ralf
R
Trautwein
Christian
C
Lammert
Frank
F
D000073883:CX3C Chemokine Receptor 1; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D019707:Receptors, Chemokine / Q000235:genetics*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D019715:Tissue Inhibitor of Metalloproteinase-1