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

Cubero Palero, Francisco Javier Kuttkat, Nadine Mohs, Antje Ohl, Kim Hooiveld, Guido Longerich, Thomas Tenbrock, Klaus Trautwein, Christian 2024-02-01T11:47:22Z 2024-02-01T11:47:22Z 2016-09-29 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 1527-3350 10.1136/ gutjnl-2015-311119 https://hdl.handle.net/20.500.14352/97617 https://gut.bmj.com/content/66/5/908 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531221/ 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. eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 International Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease journal article