1. ¹Metschnikoff Laboratory, Max-Planck-Institut for Immunbiology, Freiburg, Germany
2. ²Institute for Immunology, University Clinic Heidelberg, Heidelberg, Germany
3. ³Institute for Medical Biochemistry, ZMBE, University of Muenster, Muenster, Germany
4. ⁴German Cancer Research Center, Heidelberg, Germany
5. ⁵John Curtin School of Medical Research, Australian National University, Canberra, Australia
6. ⁶Molecular Immunology, Biology III, University of Freiburg & Max-Planck-Institut for Immunbiology, Freiburg, Germany

Correspondence: MM Simon, Metschnikoff Laboratory, Max-Planck-Institut für Immunbiologie, Stübeweg 51, Freiburg, Germany. Tel: +49-761-5108-533; Fax: +49-761-5108-529, E-mail: simon@immunbio.mpg.de

⁷These authors contributed equally to this work.

Received 8 November 2006; Revised 15 May 2007; Accepted 16 May 2007; Published online 29 June 2007.

Abstract

Mast cells respond to pathogens and allergens by secreting a vast array of preformed and newly synthesized mediators, including enzymes, vasoactive amines, lipid mediators, cytokines and chemokines, thereby affecting innate and adaptive immune responses and pathogenesis. Here, we present evidence that skin-, but not lung-associated primary mast cells as well as in vitro-differentiated bone marrow-derived mast cells (BMMC) express granzyme (gzm) B, but not gzmA or perforin (perf). GzmB is associated with cytoplasmic granules of BMMC and secreted after Fc-receptor-mediated activation. BMMC from wild type but not gzmB-deficient mice cause cell death in susceptible adherent target cells, indicating that the perf-independent cytotoxicity of BMMC is executed by gzmB. Furthermore, gzmB induces a disorganization of endothelial cell–cell contacts. The data suggest that activated mast cells contribute, via secreted gzmB, to cell death, increased vascular permeability, leukocyte extravasation and subsequent inflammatory processes in affected tissues.