Cytokine-responsive gene-2/IFN-inducible protein-10 expression in multiplemodels of liver and bile duct injury suggests a role in tissue regeneration

IFN-inducible protein-10 (IP-IO/CXCL10) is a CXC chemokine that targets bot h T cells and NK cells. Elevation of IP-10 expression has been demonstrated in a number of human diseases, including chronic cirrhosis and biliary atr esia. Cytokine-responsive gene-2 (Crg-2), the murine ortholog of IP-10, was induced following CCl4 treatment of the hepatocyte-like cell line AML-12. Crg-2 expression was noted in vivo in multiple models of hepatic and bile d uct injury, including bile duct ligation and CCl4, D-galactosamine, and met hylene dianiline toxic liver injuries. Induction of Crg-2 was also examined following two-thirds hepatectomy, a model that minimally injures the remai ning liver, but that requires a large hepatic regenerative response. Crg-2 was induced in a biphasic fashion after two-thirds hepatectomy, preceding e ach known peak of hepatocyte DNA synthesis. Induction of Crg-2 was also obs erved in the kidney, gut, thymus, and spleen within 1 h of two-thirds hepat ectomy. Characteristic of an immediate early gene, pretreatment of mice wit h the protein synthesis inhibitor cycloheximide before either two-thirds he patectomy or CCl4 injection led to Crg-2 superinduction. rIP-10 was demonst rated to have hepatocyte growth factor-inducing activity in vitro, but alon e had no direct mitogenic effect on hepatocytes. Our data demonstrate that induction of Crg-2 occurs in several distinct models of liver injury and re generation, and suggest a role for CRG-2/IP-10 in these processes. The Jour nal of Immunology, 2001.