Hepatic overexpression of cAMP-responsive element modulator α induces a regulatory T-cell response in a murine model of chronic liver disease.
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 inflammation-associated 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.



Transgenic mice overexpressing CREMα were crossed with hepatocyte-specific Nemo knockout mice (NemoΔhepa) to generate NemoΔhepa/CREMαTgmice. The impact of CREMαTgon 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.



8-week-old NemoΔhepa/CREMαTgmice presented significantly decreased transaminase levels, concomitant with reduced numbers of CD11b+dendritic cells and CD8+T cells. CREMαTgoverexpression in NemoΔhepamice 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 CREMαTghepatic T cells. Moreover, simultaneous adoptive transfer of BMDCs and T cells from CREMαTginto NemoΔhepamice ameliorated markers of liver injury and hepatitis.



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 NemoΔhepalivers towards a protective Treg response.
Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
Nadine
N
Kuttkat
Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
Antje
A
Mohs
Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany.
Kim
K
Ohl
Institute for Nutrition, Metabolism & Genomics, Wageningen University & Research Centre, Wageningen, Netherlands.
Guido
G
Hooiveld
Institute of Pathology, RWTH University Hospital Aachen, Aachen, Germany.
Thomas
T
Longerich
Department of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany.
Klaus
K
Tenbrock
Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
Francisco Javier
FJ
Cubero
Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany.
Christian
C
Trautwein
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002908:Chronic Disease; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006505:Hepatitis / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008103:Liver Cirrhosis / Q000276:immunology; D008113:Liver Neoplasms / Q000276:immunology*; D018655:Lymphocyte Count; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*
D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D051786:Cyclic AMP Response Element Modulator; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
CHRONIC LIVER DISEASE; HEPATOCELLULAR CARCINOMA; LIVER; NUCLEAR FACTOR KAPPA B; T LYMPHOCYTES
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