IFN-gamma-inducible protein-10 (CXCL10) is hepatoprotective during acute liver injury through the induction of CXCR2 on hepatocytes

IFN-gamma -inducible protein-10 (IP-10/CXCL10) is a non-ELR-CXC chemokine t hat is present during various forms of acute and chronic liver injury. The purpose of this study was to explore the role of IP-10 during acute liver i njury induced by acetaminophen (APAP). After a 400 mg/kg APAP challenge in fasted CD-1 mice, immunoreactive levels of IP-10 were dramatically elevated in the serum within 8 h. CXCR3, the receptor for IP-10, was up-regulated i n the liver. Mice that received an i.v. injection of rIP-10 10 h after APAP challenge exhibited a dramatic reduction in alanine aminotransferase 8 h l ater. Histologic analysis confirmed that the delayed IP-10 therapy dramatic ally improved the appearance of the liver when examined 48 h after APAP. Th e therapeutic effect of IP-10 was associated with a marked increase in CXCR 2 expression on hepatocytes. Neutralization of CXCR2 during IP-10 therapy r esulted in an abrogation of the hepatoprotective effect of IP-10. Furthermo re, IP-10 treatment of cultured hepatocytes stimulated a CXCR2-dependent pr oliferative response. In conclusion, IP-10 has a hepatoregenerative effect in a murine model of acute liver injury that is dependent on its up-regulat ion of CXCR2 on hepatocytes.