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 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.
Bone-Larson
C L
CL
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109,USA.
Hogaboam
C M
CM
Evanhoff
H
H
Strieter
R M
RM
Kunkel
S L
SL
D000082:Acetaminophen; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology*; D007150:Immunohistochemistry; D007700:Kinetics; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D012333:RNA, Messenger / Q000096:biosynthesis; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation
D000906:Antibodies; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B; D000082:Acetaminophen