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-Inducible Protein-10 (CXCL10) Is Hepatoprotective During Acute Liver Injury Through the Induction of CXCR2 on Hepatocytes1
*
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and
Department of Pulmonary and Critical Care Medicine, University of California, Los Angeles, CA 90095-1922
IFN-
-inducible protein-10 (IP-10/CXCL10) is a non-ELR-CXC
chemokine that 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 injury 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 in 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
later. Histologic analysis confirmed that the delayed IP-10 therapy
dramatically improved the appearance of the liver when examined 48
h after APAP. The therapeutic effect of IP-10 was associated with a
marked increase in CXCR2 expression on hepatocytes.
Neutralization of CXCR2 during IP-10 therapy resulted in an
abrogation of the hepatoprotective effect of IP-10. Furthermore, IP-10
treatment of cultured hepatocytes stimulated a CXCR2-dependent
proliferative response. In conclusion, IP-10 has a hepatoregenerative
effect in a murine model of acute liver injury that is dependent on its
up-regulation of CXCR2 on hepatocytes.
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