Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans.
OBJECTIVE
Fibrosis is the hallmark of chronic liver diseases, yet many aspects of its mechanism remain to be defined. Chemokines are ubiquitous chemotactic molecules that mediate many acute and chronic inflammatory conditions, and CXC chemokine genes colocalize with a locus previously shown to include fibrogenic genes. We investigated the roles of the chemokine CXCL9 and its receptor CXCR3 in liver fibrosis.


METHODS
The effects of CXCL variants on fibrogenesis were analyzed using samples from patients with hepatitis C virus infection and by induction of fibrosis in CXCR3(-/-) and wild-type mice. In mice, intrahepatic immune cell subsets were investigated and interferon gamma messenger RNA levels were measured at baseline and after injury. Human serum CXCL9 levels were measured and correlated with CXCL9 variant and fibrosis severity. The effects of stimulation with CXCL9 were investigated on human hepatic stellate cells (LX-2).


RESULTS
Specific CXCL9 variants were associated with liver fibrosis in mice and humans; CXCL9 serum concentrations correlated with genotypes and levels of fibrosis in patients. In contrast to other chemokines, CXCL9 exerted antifibrotic effects in vitro, suppressing collagen production in LX-2 cells. CXCR3(-/-) mice had increased liver fibrosis; progression was associated with decreased numbers of intrahepatic interferon gamma-positive T cells and reduced interferon gamma messenger RNA, indicating that CXCL9-CXCR3 regulates Th1-associated immune pathways.


CONCLUSIONS
This is the first description of a chemokine-based antifibrotic pathway in the liver; antifibrotic therapies might be developed to modulate CXC chemokine levels.
Wasmuth
Hermann E
HE
Department of Medicine III, University Hospital Aachen, Aachen, Germany. hwasmuth@ukaachen.de
Lammert
Frank
F
Zaldivar
Mirko Moreno
MM
Weiskirchen
Ralf
R
Hellerbrand
Claus
C
Scholten
David
D
Berres
Marie-Luise
ML
Zimmermann
Henning
H
Streetz
Konrad L
KL
Tacke
Frank
F
Hillebrandt
Sonja
S
Schmitz
Petra
P
Keppeler
Hildegard
H
Berg
Thomas
T
Dahl
Edgar
E
Gassler
Nikolaus
N
Friedman
Scott L
SL
Trautwein
Christian
C