title: Proapoptotic effects of the chemokine, CXCL 10 are mediated by the noncognate receptor TLR4 in hepatocytes.
abstract: Aberrant expression of the chemokine CXC chemokine ligand (CXCL)10 has been linked to the severity of hepatitis C virus (HCV)-induced liver injury, but the underlying molecular mechanisms remain unclear. In this study, we describe a yet-unknown proapoptotic effect of CXCL10 in hepatocytes, which is not mediated through its cognate chemokine receptor, but the lipopolysaccharide receptor Toll-like receptor 4 (TLR4). To this end, we investigated the link of CXCL10 expression with apoptosis in HCV-infected patients and in murine liver injury models. Mice were treated with CXCL10 or neutralizing antibody to systematically analyze effects on hepatocellular apoptosis in vivo. Direct proapoptotic functions of CXCL10 on different liver cell types were evaluated in detail in vitro. The results showed that CXCL10 expression was positively correlated with liver cell apoptosis in humans and mice. Neutralization of CXCL10 ameliorated concanavalin A-induced tissue injury in vivo, which was strongly associated with reduced liver cell apoptosis. In vitro, CXCL10 mediated the apoptosis of hepatocytes involving TLR4, but not CXC chemokine receptor 3 signaling. Specifically, CXCL10 induced long-term protein kinase B and Jun N-terminal kinase activation, leading to hepatocyte apoptosis by caspase-8, caspase-3, and p21-activated kinase 2 cleavage. Accordingly, systemic application of CXCL10 led to TLR4-induced liver cell apoptosis in vivo.
  
  
  CONCLUSIONS
  The results identify CXCL10 and its noncognate receptor, TLR4, as a proapoptotic signaling cascade during liver injury. Antagonism of the CXCL10/TLR4 pathway might be a therapeutic option in liver diseases associated with increased apoptosis.
authors.affiliation: Medical Department III and University Hospital Aachen, Aachen, Germany.
authors.forename: Hacer
authors.initials: H
authors.lastname: Sahin
authors.forename: Erawan
authors.initials: E
authors.lastname: Borkham-Kamphorst
authors.forename: Nicole T
authors.initials: NT
authors.lastname: do O
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: Berres
authors.forename: Michaela
authors.initials: M
authors.lastname: Kaldenbach
authors.forename: Petra
authors.initials: P
authors.lastname: Schmitz
authors.forename: Ralf
authors.initials: R
authors.lastname: Weiskirchen
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
authors.forename: Konrad L
authors.initials: KL
authors.lastname: Streetz
authors.forename: Kathrin
authors.initials: K
authors.lastname: Maedler
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Hermann E
authors.initials: HE
authors.lastname: Wasmuth
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000494:pharmacology*; D003208:Concanavalin A; D006526:Hepatitis C / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology* / Q000502:physiology; D006801:Humans; D008099:Liver / Q000473:pathology; D051379:Mice; D054367:Receptors, CXCR3 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D054357:Chemokine CXCL10; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D051197:Toll-Like Receptor 4; D003208:Concanavalin A; D020169:Caspases