CXC chemokine receptor-1 is expressed by hepatocytes and regulates liver recovery after hepatic ischemia/reperfusion injury.
CXC chemokines mediate hepatic inflammation and injury following ischemia/reperfusion (I/R). More recently, signaling through CXC chemokine receptor-2 (CXCR2) was shown to delay liver recovery and repair after I/R injury. The chemokine receptor CXCR1 shares ligands with CXCR2, yet nothing is known about its potential role in liver pathology. In the present study, we examined the role of CXCR1 in the injury and recovery responses to I/R using a murine model. CXCR1 expression was undetectable in livers of sham-operated mice. However, after ischemia CXCR1 expression increased 24 hours after reperfusion and was maximal after 96 hours of reperfusion. CXCR1 expression was localized largely to hepatocytes. In order to assess the function of CXCR1, CXCR2(-/-) mice were treated with the CXCR1/CXCR2 antagonist, repertaxin. Prophylactic treatment with repertaxin had no effect on acute inflammation or liver injury. However, when repertaxin was administered 24 hours postreperfusion there was a significant increase in hepatocellular injury and a delay in recovery compared to control-treated mice. CXCR1(-/-) mice also demonstrated delayed recovery and regeneration after I/R when compared to wild-type mice. In vitro, hepatocytes from CXCR2(-/-) mice that were stimulated to express CXCR1 showed increased proliferation in response to ligand. Hepatocyte proliferation was decreased in CXCR1(-/-) mice in vivo.


CONCLUSIONS
This is the first report to show that CXCR1 expression is induced in hepatocytes after injury. Furthermore, the data suggest that CXCR1 has divergent effects from CXCR2 and appears to facilitate repair and regenerative responses after I/R injury.
Laboratory of Trauma, Sepsis & Inflammation Research, Department of Surgery, University of Cincinnati, Cincinnati, OH 45267-0558, USA.
Callisia
C
Clarke
Satoshi
S
Kuboki
Nozomu
N
Sakai
Kevin R
KR
Kasten
Amit D
AD
Tevar
Rebecca
R
Schuster
John
J
Blanchard
Charles C
CC
Caldwell
Michael J
MJ
Edwards
Alex B
AB
Lentsch
D000818:Animals; D022781:Hepatocytes / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases / Q000503:physiopathology*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors; D015427:Reperfusion Injury / Q000503:physiopathology*; D013449:Sulfonamides
D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D013449:Sulfonamides; C490707:reparixin
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