Cytokine-responsive gene-2/IFN-inducible protein-10 expression in multiple models of liver and bile duct injury suggests a role in tissue regeneration.
IFN-inducible protein-10 (IP-10/CXCL10) is a CXC chemokine that targets both T cells and NK cells. Elevation of IP-10 expression has been demonstrated in a number of human diseases, including chronic cirrhosis and biliary atresia. Cytokine-responsive gene-2 (Crg-2), the murine ortholog of IP-10, was induced following CCl(4) treatment of the hepatocyte-like cell line AML-12. Crg-2 expression was noted in vivo in multiple models of hepatic and bile duct injury, including bile duct ligation and CCl(4), D-galactosamine, and methylene dianiline toxic liver injuries. Induction of Crg-2 was also examined following two-thirds hepatectomy, a model that minimally injures the remaining liver, but that requires a large hepatic regenerative response. Crg-2 was induced in a biphasic fashion after two-thirds hepatectomy, preceding each known peak of hepatocyte DNA synthesis. Induction of Crg-2 was also observed in the kidney, gut, thymus, and spleen within 1 h of two-thirds hepatectomy. Characteristic of an immediate early gene, pretreatment of mice with the protein synthesis inhibitor cycloheximide before either two-thirds hepatectomy or CCl(4) injection led to Crg-2 superinduction. rIP-10 was demonstrated to have hepatocyte growth factor-inducing activity in vitro, but alone had no direct mitogenic effect on hepatocytes. Our data demonstrate that induction of Crg-2 occurs in several distinct models of liver injury and regeneration, and suggest a role for CRG-2/IP-10 in these processes.
Koniaris
L G
LG
Departments of Molecular Biology and Genetics and Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. leonidas_koniaris@urmc.rochester.edu
Zimmers-Koniaris
T
T
Hsiao
E C
EC
Chavin
K
K
Sitzmann
J V
JV
Farber
J M
JM
D000818:Animals; D001652:Bile Ducts / Q000276:immunology / Q000473:pathology*; D002251:Carbon Tetrachloride / Q000633:toxicity; D002458:Cell Fractionation; D002460:Cell Line; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000502:physiology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000276:immunology; D017781:Genes, Immediate-Early; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D006801:Humans; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008105:Liver Cirrhosis, Biliary / Q000276:immunology; D017093:Liver Failure / Q000276:immunology; D008115:Liver Regeneration / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008934:Mitogens / Q000096:biosynthesis / Q000502:physiology; D015846:Monokines / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D014945:Wound Healing / Q000276:immunology
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; D008934:Mitogens; D015846:Monokines; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; D002251:Carbon Tetrachloride