title: CD13/aminopeptidase N is a negative regulator of mast cell activation.
abstract: Antigen-induced mast cell (MC) activation via cross-linking of IgE-bound high-affinity receptors for IgE (FcεRI) underlies type I allergy and anaphylactic shock. Comprehensive knowledge of FcεRI regulation is thus required. We have identified a functional interaction between FcεRI and CD13 in murine MCs. Antigen-triggered activation of IgE-loaded FcεRI results in cocapping and cointernalization of CD13 and equivalent internalization rates of up to 40%. Cointernalization is not unspecific, because ligand-driven KIT internalization is not accompanied by CD13 internalization. Moreover, antibody-mediated cross-linking of CD13 causes IL-6 production in an FcεRI-dependent manner. These data are indicative of a functional interaction between FcεRI and CD13 on MCs. To determine the role of this interaction, CD13-deficient bone marrow-derived MCs (BMMCs) were analyzed. Intriguingly, antigen stimulation of CD13-deficient BMMCs results in significantly increased degranulation and proinflammatory cytokine production compared to wild-type cells. Furthermore, in a low-dose model of passive systemic anaphylaxis, antigen-dependent decrease in body temperature, reflecting the anaphylactic reaction, is substantially enhanced by the CD13 inhibitor bestatin (-5.9 ± 0.6°C) and by CD13 deficiency (-8.8 ± 0.6°C) in contrast to controls (-1.2 ± 1.97°C). Importantly, bestatin does not aggravate anaphylaxis in CD13-deficient mice. Thus, we have identified CD13 as a novel negative regulator of MC activation in vitro and in vivo-Zotz, J. S., Wölbing, F., Lassnig, C., Kauffmann, M., Schulte, U., Kolb, A., Whitelaw, B., Müller, M., Biedermann, T., Huber, M. CD13/aminopeptidase N is a negative regulator of mast cell activation.
authors.affiliation: Institute of Biochemistry and Molecular Immunology, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany;
authors.forename: Julia S
authors.initials: JS
authors.lastname: Zotz
authors.affiliation: Department of Dermatology, Technical University of Munich, Munich, Germany;
authors.forename: Florian
authors.initials: F
authors.lastname: Wölbing
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria;
authors.forename: Caroline
authors.initials: C
authors.lastname: Lassnig
authors.affiliation: Institute of Biochemistry and Molecular Immunology, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany;
authors.forename: Marlies
authors.initials: M
authors.lastname: Kauffmann
authors.affiliation: Institute of Physiology II, University of Freiburg, Freiburg, Germany; Centre for Biological Signalling Studies (Bioss), Freiburg, Germany; Logopharm GmbH, March-Buchheim, Germany;
authors.forename: Uwe
authors.initials: U
authors.lastname: Schulte
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, United Kingdom; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kolb
authors.affiliation: The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Bruce
authors.initials: B
authors.lastname: Whitelaw
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, Austria;
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Dermatology, Technical University of Munich, Munich, Germany;
authors.forename: Tilo
authors.initials: T
authors.lastname: Biedermann
authors.affiliation: Institute of Biochemistry and Molecular Immunology, University Hospital, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany; mhuber@ukaachen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Huber
mesh_terms: D000707:Anaphylaxis; D000818:Animals; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D004140:Dinitrophenols / Q000276:immunology; D005786:Gene Expression Regulation / Q000502:physiology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008264:Macrophages; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017455:Receptors, IgE / Q000235:genetics / Q000378:metabolism; D012709:Serum Albumin / Q000276:immunology
chemical_list: D004140:Dinitrophenols; D017455:Receptors, IgE; D012709:Serum Albumin; C058064:dinitrophenyl-human serum albumin conjugate; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex
keywords: IgE receptor; degranulation; passive systemic anaphylaxis; proinflammatory cytokines; receptor internalization