title: The cAMP response element modulator (CREM) regulates TH2 mediated inflammation.
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.
authors.affiliation: Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.|Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Verjans
authors.affiliation: Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.
authors.forename: Kim
authors.initials: K
authors.lastname: Ohl
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany.
authors.forename: Lucy K
authors.initials: LK
authors.lastname: Reiss
authors.affiliation: Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Femke
authors.initials: F
authors.lastname: van Wijk
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children`s Hospital Regensburg (KUNO), Regensburg, Germany.
authors.forename: Antonaneta A
authors.initials: AA
authors.lastname: Toncheva
authors.affiliation: Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Wiener
authors.affiliation: Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.
authors.forename: Yin
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany.|Department of Anaesthesiology, Medical Faculty, RWTH Aachen, Aachen, Germany.
authors.forename: Annette D
authors.initials: AD
authors.lastname: Rieg
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children`s Hospital Regensburg (KUNO), Regensburg, Germany.
authors.forename: Vincent D
authors.initials: VD
authors.lastname: Gaertner
authors.affiliation: Institute of Immunology, University of Münster, Münster, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: Department of Pediatric Immunology, University Medical Center Utrecht, Utrecht, Netherlands.
authors.forename: Edward
authors.initials: E
authors.lastname: Knol
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children`s Hospital Regensburg (KUNO), Regensburg, Germany.|Member of The German Lung Research Center (DZL), Gießen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.affiliation: Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Wagner
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.affiliation: Institute of Pharmacology and Toxicology, RWTH Aachen, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Martin
authors.affiliation: Department of Pediatrics, Medical Faculty, RWTH Aachen, Aachen, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Tenbrock
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001249:Asthma / Q000276:immunology; D002648:Child; D051786:Cyclic AMP Response Element Modulator / Q000096:biosynthesis / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018418:Th2 Cells / Q000276:immunology*; D055815:Young Adult
chemical_list: C497410:CREM protein, human; D016207:Cytokines; D051786:Cyclic AMP Response Element Modulator
keywords: Immune response; Immunity; Immunology Section; T cell dysregulation; TH2; allergic disease; asthmatic response; transcription factor