Expression of the CXCR3 ligand I-TAC by hepatocytes in chronic hepatitis C and its correlation with hepatic inflammation.
The factors that regulate lymphocyte traffic in chronic hepatitis C (CHC) are not completely defined. Interferon (IFN)-inducible T cell alpha chemoattractant (I-TAC) is a relatively new member of the CXCR3 chemokine ligand family that selectively recruits activated T cells to sites of inflammation. To determine if I-TAC plays a role in CHC, we investigated I-TAC expression in hepatitis C virus (HCV)-infected liver biopsy material. I-TAC messenger RNA (mRNA) levels were significantly increased in HCV-infected liver compared with normal liver, which correlated with both portal and lobular inflammation. I-TAC expression was localized to hepatocytes throughout the liver lobule, with those in close proximity to active areas of inflammation expressing the highest concentration of I-TAC. In vitro, I-TAC mRNA and protein expression was inducible in Huh-7 cells following either IFN-alpha or -gamma stimulation and synergistically with tumor necrosis factor (TNF)-alpha. Furthermore, transfection of Huh-7 cells with either poly(I:C) or HCV RNA representing the HCV subgenomic replicon induced I-TAC mRNA expression. HCV replication was also found to modulate I-TAC expression, with stimulation of Huh-7 cells harboring either the HCV subgenomic or genomic replicon showing significantly increased synergistic effects compared with those previously seen in Huh-7 cells alone with IFN-gamma and TNF-alpha. In conclusion, these results suggest I-TAC, one of the most potent chemoattractants for activated T cells, is produced by hepatocytes in the HCV-infected liver and plays an important role in T cell recruitment and ultimately the pathogenesis of CHC.
Helbig
Karla J
KJ
Infectious Diseases Laboratories, Adelaide, Australia.
Ruszkiewicz
Andrew
A
Semendric
Ljiljana
L
Harley
Hugh A J
HA
McColl
Shaun R
SR
Beard
Michael R
MR
D000998:Antiviral Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D016174:Hepacivirus / Q000235:genetics* / Q000254:growth & development; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000503:physiopathology*; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D016898:Interferon-alpha / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D008113:Liver Neoplasms; D012330:RNA, Double-Stranded / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism*; D012093:Replicon; D015854:Up-Regulation
D000998:Antiviral Agents; C515202:CXCL11 protein, human; C515187:CXCR3 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; D016898:Interferon-alpha; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D012367:RNA, Viral; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D007371:Interferon-gamma