Oncotarget

Research Papers: Immunology:

The cAMP response element modulator (CREM) regulates TH2 mediated inflammation

Eva Verjans, Kim Ohl, Lucy K. Reiss, Femke van Wijk, Antonaneta A. Toncheva, Anastasia Wiener, Yin Yu, Annette D. Rieg, Vincent D. Gaertner, Johannes Roth, Edward Knol, Michael Kabesch, Norbert Wagner, Stefan Uhlig, Christian Martin _ and Klaus Tenbrock

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Oncotarget. 2015; 6:38538-38551. https://doi.org/10.18632/oncotarget.6041

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Abstract

Eva Verjans1,2,*, Kim Ohl1,*, Lucy K. Reiss2, Femke van Wijk3, Antonaneta A. Toncheva4, Anastasia Wiener1, Yin Yu1, Annette D. Rieg2,5, Vincent D. Gaertner4, Johannes Roth6, Edward Knol3, Michael Kabesch4,7, Norbert Wagner1, Stefan Uhlig2, Christian Martin2,** and Klaus Tenbrock1,**

1 Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany

2 Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany

3 Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, Netherlands

4 Department of Pediatric Pneumology and Allergy, University Children`s Hospital Regensburg (KUNO), Regensburg, Germany

5 Department of Anaesthesiology, Medical Faculty, RWTH Aachen, Aachen, Germany

6 Institute of Immunology, University of Münster, Münster, Germany

7 Member of the German Lung Research Center (DZL), Gießen, Germany

* These authors contributed equally to this project and should be considered as co-first authors

** These authors contributed equally to this project and should be considered as co-senior author

Correspondence to:

Christian Martin, email:

Keywords: allergic disease, asthmatic response, T cell dysregulation, transcription factor, TH2, Immunology Section, Immunity, Immune response

Received: August 06, 2015 Accepted: September 17, 2015 Published: October 08, 2015

Abstract

A characteristic feature of allergic diseases is the appearance of a subset of CD4+ cells known as TH2 cells, which is controlled by transcriptional and epigenetic mechanisms. We aimed to analyze the role of CREM, a known transcriptional activator of T cells, with regard to TH2 responses and allergic diseases in men and mice. Here we demonstrate that T cells of asthmatic children and PBMCs of adults with atopy express lower mRNA levels of the transcription factor CREM compared to cells from healthy controls. CREM deficiency in murine T cells results in enhanced TH2 effector cytokines in vitro and in vivo and CREM-/- mice demonstrate stronger airway hyperresponsiveness in an OVA-induced asthma model. Mechanistically, both direct CREM binding to the IL-4 and IL-13 promoter as well as a decreased IL-2 dependent STAT5 activation suppress the TH2 response. Accordingly, mice selectively overexpressing CREMα in T cells display decreased TH2 type cytokines in vivo and in vitro, and are protected in an asthma model. Thus, we provide evidence that CREM is a negative regulator of the TH2 response and determines the outcome of allergic asthma.


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