RT Journal Article
T1 Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease
A1 Cubero Palero, Francisco Javier
A1 Kuttkat, Nadine
A1 Mohs, Antje
A1 Ohl, Kim
A1 Hooiveld, Guido
A1 Longerich, Thomas
A1 Tenbrock, Klaus
A1 Trautwein, Christian
AB 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 vitrostudies, 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, simultaneousadoptive 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 theinflammatory 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.
PB Lippincott, Williams & Wilkins
SN 1527-3350
YR 2016
FD 2016-09-29
LK https://hdl.handle.net/20.500.14352/97617
UL https://hdl.handle.net/20.500.14352/97617
LA eng
NO 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
NO 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, Germany2 Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany3 Institute for Nutrition, Metabolism & Genomics, Wageningen University & Research Centre, Wageningen, Netherlands4 Institute of Pathology, RWTH University Hospital Aachen, Aachen, GermanyCorrespondence to Professor Christian Trautwein, Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, Aachen D-52074, Germany; ctrautwein@ukaachen.deFrancisco Javier Cubero, Department of Immunology, Complutense University School of Medicine, Plaza de Ramón y Cajal s/n, Madrid 28040, Spain; fcubero@ucm.esNK and AM contributed equally. FJC and CT are joint senior authors.
NO ZKF (UKA, RWTH Aachen)
DS Docta Complutense
RD 17 dic 2025