Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C.
Chemokines, chemotactic cytokines, may promote hepatic inflammation in chronic hepatitis C virus (HCV) infection through the recruitment of lymphocytes to the liver parenchyma. We evaluated the association between inflammation and fibrosis and CXCR3-associated chemokines, interferon-gamma (IFN-gamma)-inducible protein 10 (IP-10/CXCL10), monokine induced by IFN-gamma (Mig/CXCL9), and interferon-inducible T cell alpha chemoattractant (I-TAC/CXCL11), in HCV infection. Intrahepatic mRNA expression of these chemokines was analyzed in 106 chronic HCV-infected patients by real-time PCR. The intrahepatic localization of chemokine producer cells and CXCR3(+) lymphocytes was determined in selected patients by immunohistochemistry. We found elevated intrahepatic mRNA expression of all three chemokines, most markedly CXCL10, in chronic HCV-infected patients with higher necroinflammation and fibrosis. By multivariable multivariate analysis, intrahepatic CXCL10 mRNA expression levels were significantly associated with lobular necroinflammatory grade and HCV genotype 1. In the lobular region, CXCL10-expressing and CXCL9-expressing hepatocytes predominated in areas with necroinflammation. Strong CXCL11 expression was observed in almost all portal tracts, whereas CXCL9 expression varied considerably among portal tracts in the same individual. Most intrahepatic lymphocytes express the CXCR3 receptor, and the number of CXCR3(+) lymphocytes was increased in patients with advanced necroinflammation.


CONCLUSIONS
These findings suggest that the CXCR3-associated chemokines, particularly CXCL10, may play an important role in the development of necroinflammation and fibrosis in the liver parenchyma in chronic HCV infection.
Zeremski
Marija
M
Department of Medicine, Division of Gastroenterology and Hepatology, The Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY 10065, USA.
Petrovic
Lydia M
LM
Chiriboga
Luis
L
Brown
Queenie B
QB
Yee
Herman T
HT
Kinkhabwala
Milan
M
Jacobson
Ira M
IM
Dimova
Rositsa
R
Markatou
Marianthi
M
Talal
Andrew H
AH
D000328:Adult; D000368:Aged; D001706:Biopsy; D054357:Chemokine CXCL10 / Q000502:physiology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D018925:Chemokines; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D012313:RNA
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