title: CXC chemokines function as a rheostat for hepatocyte proliferation and liver regeneration.
abstract: BACKGROUND
  Our previous in vitro studies have demonstrated dose-dependent effects of CXCR2 ligands on hepatocyte cell death and proliferation. In the current study, we sought to determine if CXCR2 ligand concentration is responsible for the divergent effects of these mediators on liver regeneration after ischemia/reperfusion injury and partial hepatectomy.
  
  
  METHODS
  Murine models of partial ischemia/reperfusion injury and hepatectomy were used to study the effect of CXCR2 ligands on liver regeneration.
  
  
  RESULTS
  We found that hepatic expression of the CXCR2 ligands, macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC), was significantly increased after both I/R injury and partial hepatectomy. However, expression of these ligands after I/R injury was 30-100-fold greater than after hepatectomy. Interestingly, the same pattern of expression was found in ischemic versus non-ischemic liver lobes following I/R injury with expression significantly greater in the ischemic liver lobes. In both systems, lower ligand expression was associated with increased hepatocyte proliferation and liver regeneration in a CXCR2-dependent fashion. To confirm that these effects were related to ligand concentration, we administered exogenous MIP-2 and KC to mice undergoing partial hepatectomy. Mice received a "high" dose that replicated serum levels found after I/R injury and a "low" dose that was similar to that found after hepatectomy. Mice receiving the "high" dose had reduced levels of hepatocyte proliferation and regeneration whereas the "low" dose promoted hepatocyte proliferation and regeneration.
  
  
  CONCLUSIONS
  Together, these data demonstrate that concentrations of CXC chemokines regulate the hepatic proliferative response and subsequent liver regeneration.
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Wilson
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kuboki
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nojima
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Schuster
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America.
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D054426:Chemokine CXCL2 / Q000494:pharmacology; D022781:Hepatocytes / Q000502:physiology*; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008115:Liver Regeneration; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D023063:Receptors, Interleukin-8B / Q000502:physiology*; D015427:Reperfusion Injury / Q000378:metabolism
chemical_list: D054426:Chemokine CXCL2; D023063:Receptors, Interleukin-8B