title: Colonic expression of the peptide transporter PEPT1 is downregulated during intestinal inflammation and is not required for NOD2-dependent immune activation.
abstract: BACKGROUND
  PEPT1 was proposed to be expressed only in inflamed colonic tissues in which it could contribute to inflammatory bowel disease (IBD) development by transporting bacterial peptides, such as muramyl dipeptide (MDP), that activate intracellular pattern recognition receptors, such as the nucleotide-binding and oligomerization domain 2. To better define the pathological relevance of this transporter, we analyzed PEPT1 expression during intestinal inflammation and studied the susceptibility of Pept1-deficient (Pept1) mice to experimental colitis.
  
  
  METHODS
  Wild-type and Pept1 mice were treated with dextran sulfate sodium and 2,4,6-trinitrobenzene sulfonic acid to induce colitis, and MDP-induced cytokine expression was studied in colonic tissue cultures. PEPT1 expression was characterized in mouse models of Crohn's disease-like ileitis (Tnf) or colitis (Il-10, Il-10XTlr2) and endoscopic tissue samples from descending colon of patients with IBD (n = 11) and controls (n = 17). Moreover, the prevalence of the PEPT1 single-nucleotide polymorphism rs2297322 was tested in German patients with IBD (n = 458) and controls (n = 452).
  
  
  RESULTS
  PEPT1 expression was consistently reduced under condition of acute or chronic experimental inflammation. Wild-type and Pept1 mice revealed comparable susceptibility to dextran sulfate sodium-induced and 2,4,6-trinitrobenzene sulfonic acid-induced colitis, and MDP-induced cytokine expression was PEPT1-independent. PEPT1 expression levels were also decreased in descending colon of patients with IBD during acute inflammation, but the rs2297322 single-nucleotide polymorphism was not associated with IBD susceptibility in the German cohort.
  
  
  CONCLUSIONS
  PEPT1 expression is reduced during intestinal inflammation and PEPT1 is neither required for MDP-induced immune response nor is the PEPT1 rs2297322 single-nucleotide polymorphism associated with IBD susceptibility in our German cohort. These data strongly argue against a primary role of PEPT1 in the initiation or progression of IBD.
authors.affiliation: 1Technische Universität München, ZIEL-Research Center for Nutrition and Food Science, Biochemistry Unit, Weihenstephan, Germany; 2Institute of Pathology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; 3Institut Pasteur de Lille, Center for Infection and Immunity of Lille, Lille, France; 4Université Lille Nord de France, Lille, France; 5Centre national de la recherche scientifique, Unité Mixte de Recherche, Lille, France; 6Institut National de la Santé et de la Recherche Médicale, Lille, France; 7Technische Universität München, ZIEL-Research Center for Nutrition and Food Science, Biofunctionality Unit, Weihenstephan, Germany; 8Institute of Microbiology and Hygiene, Charité-Universitätsmedizin Berlin, Campus Benjamin-Franklin, Berlin, Germany; 9Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina; 10Department of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany; 11Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, Heidelberg University, German Red Cross Blood Service of Baden-Württemberg-Hessen, Mannheim, Germany; 12Else Kröner-Fresenius-Zentrum für Ernährungsmedizin (EKFZ) and ZIEL-Research Center for Nutrition and Food Science, Technische Universität München (TUM), Weihenstephan, Germany; and 13Department of Pediatrics, Klinikum rechts der Isar (MRI), Technische Universität München (TUM), Munich, Germany. T. Wuensch is now with Department of Cell and Molecular Biology, Karolinska Institute, von Eulersväg 3, Stockholm, Sweden.
authors.forename: Tilo
authors.initials: T
authors.lastname: Wuensch
authors.forename: Sina
authors.initials: S
authors.lastname: Ullrich
authors.forename: Stephan
authors.initials: S
authors.lastname: Schulz
authors.forename: Mathias
authors.initials: M
authors.lastname: Chamaillard
authors.forename: Nicola
authors.initials: N
authors.lastname: Schaltenberg
authors.forename: Eva
authors.initials: E
authors.lastname: Rath
authors.forename: Ulf
authors.initials: U
authors.lastname: Goebel
authors.forename: R Balfour
authors.initials: RB
authors.lastname: Sartor
authors.forename: Matthias
authors.initials: M
authors.lastname: Prager
authors.forename: Carsten
authors.initials: C
authors.lastname: Büning
authors.forename: Peter
authors.initials: P
authors.lastname: Bugert
authors.forename: Heiko
authors.initials: H
authors.lastname: Witt
authors.forename: Dirk
authors.initials: D
authors.lastname: Haller
authors.forename: Hannelore
authors.initials: H
authors.lastname: Daniel
mesh_terms: D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism*; D003424:Crohn Disease / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D005838:Genotype; D006801:Humans; D007079:Ileitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018928:Immunity, Mucosal / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000074011:Peptide Transporter 1; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014302:Trinitrobenzenesulfonic Acid; D055815:Young Adult
chemical_list: D016207:Cytokines; D053473:Nod2 Signaling Adaptor Protein; D000074011:Peptide Transporter 1; D012333:RNA, Messenger; D027981:Symporters; D000119:Acetylmuramyl-Alanyl-Isoglutamine; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate