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

// Eva Verjans 1,2,* , Kim Ohl 1,* , Lucy K. Reiss 2 , Femke van Wijk 3 , Antonaneta A. Toncheva 4 , Anastasia Wiener 1 , Yin Yu 1 , Annette D. Rieg 2,5 , Vincent D. Gaertner 4 , Johannes Roth 6 , Edward Knol 3 , Michael Kabesch 4,7 , Norbert Wagner 1 , Stefan Uhlig 2 , Christian Martin 2,** and Klaus Tenbrock 1,** 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 Munster, Munster, Germany 7 Member of the German Lung Research Center (DZL), Giesen, 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, T H 2, 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 T H 2 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 T H 2 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 T H 2 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 T H 2 response. Accordingly, mice selectively overexpressing CREMα in T cells display decreased T H 2 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 T H 2 response and determines the outcome of allergic asthma.