2026-07-31T09:26:56Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/976172024-02-15T01:27:12Zcom_20.500.14352_14col_20.500.14352_15

Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease Cubero Palero, Francisco Javier Kuttkat, Nadine Mohs, Antje Ohl, Kim Hooiveld, Guido Longerich, Thomas Tenbrock, Klaus Trautwein, Christian 577 Hepatocellular Carcinoma Chronic liver disease Liver Nuclear factor Kappa B T Lymphocytes Ciencias Biomédicas Biología Biología celular (Biología) Medicina Gastroenterología y hepatología Inmunología 24 Ciencias de la Vida 2407 Biología Celular 2407.99 Otras 2412 Inmunología 2415 Biología Molecular 3299 Otras Especialidades Médicas Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/gutjnl-2015-311119). 1 Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany 2 Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany 3 Institute for Nutrition, Metabolism & Genomics, Wageningen University & Research Centre, Wageningen, Netherlands 4 Institute of Pathology, RWTH University Hospital Aachen, Aachen, Germany Correspondence to Professor Christian Trautwein, Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, Aachen D-52074, Germany; ctrautwein@ukaachen.de Francisco Javier Cubero, Department of Immunology, Complutense University School of Medicine, Plaza de Ramón y Cajal s/n, Madrid 28040, Spain; fcubero@ucm.es NK and AM contributed equally. FJC and CT are joint senior authors. Objective: Th17 cells are a subset of CD4+ T-helper cells characterised by interleukin 17 (IL-17) production, a cytokine that plays a crucial role in inflammationassociated diseases. The cyclic AMP-responsive element modulator-α (CREMα) is a central mediator of T-cell pathogenesis, which contributes to increased IL-17 expression in patients with autoimmune disorders. Since an increased Th17 response is associated with a poor prognosis in patients with chronic liver injury, we investigated the relevance of Th17 cells for chronic liver disease (CLD) and hepatocarcinogenesis. Design: Transgenic mice overexpressing CREMα were crossed with hepatocyte-specific Nemo knockout mice (NemoΔhepa) to generate NemoΔhepa/CREMαTg mice. The impact of CREMαTg on CLD progression was examined. Additionally, soft agar colony formation assays, in vitro studies, adoptive transfer of bone marrow-derived cells (BMDCs) and T cells, and gene arrays in T cells were performed. Results: 8-week-old NemoΔhepa/CREMαTg mice presented significantly decreased transaminase levels, concomitant with reduced numbers of CD11b+ dendritic cells and CD8+ T cells. CREMαTg overexpression in NemoΔhepa mice was associated with significantly reduced hepatic fibrogenesis and carcinogenesis at 52 weeks. Interestingly, hepatic stellate cell-derived retinoic acid induced a regulatory T-cell (Treg) phenotype in CREMαTg hepatic T cells. Moreover, simultaneous adoptive transfer of BMDCs and T cells from CREMαTg into NemoΔhepa mice ameliorated markers of liver injury and hepatitis. Conclusions: Our results demonstrate that overexpression of CREMα in T cells changes the inflammatory milieu, attenuating initiation and progression of CLD. Unexpectedly, our study indicates that CREMα transgenic T cells shift chronic inflammation in NemoΔhepa livers towards a protective Treg response. ZKF (UKA, RWTH Aachen) Depto. de Inmunología, Oftalmología y ORL Fac. de Medicina TRUE pub 2024-02-01T11:47:22Z 2024-02-01T11:47:22Z 2016-09-29 journal article VoR https://hdl.handle.net/20.500.14352/97617 1527-3350 10.1136/ gutjnl-2015-311119 eng #691405 Kuttkat N, Mohs A, Ohl K, Hooiveld G, Longerich T, Tenbrock K, Cubero FJ, Trautwein C. Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease. Gut. 2017 May;66(5):908-919. doi: 10.1136/gutjnl-2015-311119 Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ open access application/pdf Lippincott, Williams & Wilkins