title: Functional role of CCL5/RANTES for HCC progression during chronic liver disease.
abstract: During liver inflammation, triggering fibrogenesis and carcinogenesis immune cells play a pivotal role. In the present study we investigated the role of CCL5 in human and in murine models of chronic liver inflammation leading to hepatocellular carcinoma (HCC) development.
  
  
  
  CCL5 expression and its receptors were studied in well-defined patients with chronic liver disease (CLD) and in two murine inflammation based HCC models. The role of CCL5 in inflammation, fibrosis, tumor initiation and progression was analyzed in different cell populations of NEMOΔhepa/CCL5-/-animals and after bone marrow transplantation (BMT). For therapeutic intervention Evasin-4 was injected for 24h or 8weeks.
  
  
  
  In CLD patients, CCL5 and its receptor CCR5 are overexpressed - an observation confirmed in the Mdr2-/-and NEMOΔhepamodel. CCL5 deletion in NEMOΔhepamice diminished hepatocyte apoptosis, compensatory proliferation and fibrogenesis due to reduced immune cell infiltration. Especially, CD45+/Ly6G+granulocytes, CD45+/CD11b+/Gr1.1+/F4/80+pro-inflammatory monocytes, CD4+and CD8+T cells were decreased. One year old NEMOΔhepa/CCL5-/-mice displayed smaller and less malignant tumors, characterized by reduced proliferative capacity and less pronounced angiogenesis. We identified hematopoietic cells as the main source of CCL5, while CCL5 deficiency did not sensitise NEMOΔhepahepatocytes towards TNFα induced apoptosis. Finally, therapeutic intervention with Evasin-4 over a period of 8weeks ameliorated liver disease progression.
  
  
  
  We identified an important role of CCL5 in human and functionally in mice with disease progression, especially HCC development. A novel approach to inhibit CCL5 in vivo thus appears encouraging for patients with CLD.
  
  
  
  Our present study identifies the essential role of the chemoattractive cytokine CCL5 for liver disease progression and especially hepatocellular carcinoma development in men and mice. Finally, the inhibition of CCL5 appears to be encouraging for therapy of human chronic liver disease.
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Mohs
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Kuttkat
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Reißing
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Henning Wolfgang
authors.initials: HW
authors.lastname: Zimmermann
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Sonntag
authors.affiliation: Merck Serono Geneva Research Centre, Case postale 54, chemin des Mines 9, Geneva CH-1211 20, Switzerland.
authors.forename: Amanda
authors.initials: A
authors.lastname: Proudfoot
authors.affiliation: Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3508 TB Utrecht, The Netherlands.
authors.forename: Sameh A
authors.initials: SA
authors.lastname: Youssef
authors.affiliation: Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3508 TB Utrecht, The Netherlands; University Medical Center Groningen, Department of Pediatrics, University of Groningen, NL-9713 Groningen, The Netherlands.
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Cubero
authors.affiliation: Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany. Electronic address: ctrautwein@ukaachen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D006410:Hematopoiesis / Q000276:immunology; D006521:Hepatitis, Chronic / Q000150:complications / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000276:immunology / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D008114:Liver Neoplasms, Experimental / Q000209:etiology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism
chemical_list: C483024:CCL5 protein, human; C000592874:CCR5 protein, mouse; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D012333:RNA, Messenger; D019713:Receptors, CCR5
keywords: Fibrosis therapy; HCC; Inflammation; NFkB signaling