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Functional role of CCL5/RANTES for HCC progression during chronic liver disease

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dc.contributor.authorMohs, Antje
dc.contributor.authorKuttkat, Nadine
dc.contributor.authorReißing, Johanna
dc.contributor.authorWolfgang Zimmermann, Henning
dc.contributor.authorSonntag, Roland
dc.contributor.authorProudfoot, Amanda
dc.contributor.authorYoussef, Sameh A.
dc.contributor.authorde Bruin, Alain
dc.contributor.authorCubero Palero, Francisco Javier
dc.contributor.authorTrautwein, Christian
dc.date.accessioned2024-02-01T11:23:46Z
dc.date.available2024-02-01T11:23:46Z
dc.date.issued2016
dc.description2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Instituciones participantes: 1Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany; 2Merck Serono Geneva Research Centre, Case postale 54, chemin des Mines 9, Geneva CH-1211 20, Switzerland; 3Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 1, 3508 TB Utrecht, The Netherlands; 4University Medical Center Groningen, Department of Pediatrics, University of Groningen, NL-9713 Groningen, The Netherlands
dc.description.abstractBackground & Aims: 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. Methods: 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 NEMODhepa/CCL5-/- animals and after bone marrow transplantation (BMT). For therapeutic intervention Evasin-4 was injected for 24 h or 8 weeks. Results: In CLD patients, CCL5 and its receptor CCR5 are overexpressed – an observation confirmed in the Mdr2-/- and NEMODhepa model. CCL5 deletion in NEMODhepa mice diminished hepatocyte apoptosis, compensatory proliferation and fibrogenesis due to reduced immune cell infiltration. Especially, CD45+/Ly6G+granulocytes, CD45+/CD11b+/Gr1.1+/F4/80+ proinflammatory monocytes, CD4+ and CD8+ T cells were decreased. One year old NEMODhepa/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 NEMODhepa hepatocytes towards TNFa induced apoptosis. Finally, therapeutic intervention with Evasin-4 over a period of 8 weeks ameliorated liver disease progression. Conclusion: 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. Lay summary: 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.
dc.description.departmentDepto. de Inmunología, Oftalmología y ORL
dc.description.facultyFac. de Medicina
dc.description.refereedTRUE
dc.description.sponsorshipUniversität Münster
dc.description.statuspub
dc.identifier.citationMohs A, Kuttkat N, Reißing J, Zimmermann HW, Sonntag R, Proudfoot A, Youssef SA, de Bruin A, Cubero FJ, Trautwein C. Functional role of CCL5/RANTES for HCC progression during chronic liver disease. J Hepatol. 2017 Apr;66(4):743-753. doi: 10.1016/j.jhep.2016.12.011. Epub 2016 Dec 21. PMID: 28011329.
dc.identifier.doi10.1016/j.jhep.2016.12.011
dc.identifier.issn0168-8278
dc.identifier.officialurlhttps://doi.org/10.1016/j.jhep.2016.12.011
dc.identifier.pmid28011329
dc.identifier.relatedurlhttps://pubmed.ncbi.nlm.nih.gov/28011329/
dc.identifier.urihttps://hdl.handle.net/20.500.14352/97592
dc.journal.titleJournal of Hepatology
dc.language.isoeng
dc.page.final753
dc.page.initial743
dc.publisherElsevier
dc.rights.accessRightsrestricted access
dc.subject.cdu616.36
dc.subject.keywordFibrosis therapy
dc.subject.keywordHCC
dc.subject.keywordInflammation
dc.subject.keywordNFkB signaling
dc.subject.ucmInmunología
dc.subject.ucmCiencias Biomédicas
dc.subject.ucmBiología
dc.subject.ucmBiología celular (Biología)
dc.subject.ucmBiología molecular (Biología)
dc.subject.ucmGastroenterología y hepatología
dc.subject.unesco24 Ciencias de la Vida
dc.subject.unesco2407 Biología Celular
dc.subject.unesco2407.99 Otras
dc.subject.unesco2410 Biología Humana
dc.subject.unesco2412 Inmunología
dc.subject.unesco2415 Biología Molecular
dc.subject.unesco3299 Otras Especialidades Médicas
dc.titleFunctional role of CCL5/RANTES for HCC progression during chronic liver disease
dc.typejournal article
dc.type.hasVersionVoR
dc.volume.number66
dspace.entity.typePublication
relation.isAuthorOfPublicationb3877679-0fbd-42e6-8541-1efeb2df768a
relation.isAuthorOfPublication.latestForDiscoveryb3877679-0fbd-42e6-8541-1efeb2df768a

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