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Selective Activation of Human Intestinal Mast Cells by Escherichia coli Hemolysin¹

Sigrid Krämer^2,*, Gernot Sellge^2,, Axel Lorentz^*, Dagmar Krueger, Michael Schemann, Katharina Feilhauer, Florian Gunzer^¶ and Stephan C. Bischoff^3,*

^* Department of Nutritional Medicine and Immunology, University of Hohenheim, Stuttgart, Germany; Pathogénie Microbienne Moléculaire-Institut National de la Santé et de la Recherche Médicale Unité 786, Institut Pasteur, Paris, France; Department of Human Biology, Technical University Munich, Munich, Germany; Clinic for Visceral Surgery, Katharinenhospital, Stuttgart, Germany; and ^¶ Institute of Medical Microbiology and Hygiene, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany

Mast cells (MCs) are recognized to play an important role in bacterial host defense in the murine system. In this study, we studied the interaction of human MCs, isolated from the intestine and purified to homogeneity, with different Escherichia coli and Shigella flexneri strains. We show that -hemolysin (Hly)-producing E. coli strains induce the release of histamine, leukotrienes, and proinflammatory cytokines in intestinal MCs. In contrast, MCs were virtually unresponsive to S. flexneri and several Hly-negative E. coli strains, including the isogenic Hly-deficient mutants of Hly⁺ strains. Hly⁺ E. coli but not Hly^– E. coli caused an increase in intracellular Ca²⁺ levels. Blocking of extracellular Ca²⁺ and of the calmodulin/calcineurin pathway by cyclosporin A inhibited the response to Hly⁺ E. coli. Furthermore, inhibition of MAPKs p38 and ERK reduces activation of MCs by Hly⁺ E. coli. In addition, using an ex vivo system, we directly record the histamine release by MCs located in the lamina propria after infection with Hly⁺ E. coli. Our data indicate that human intestinal mast cells interact with selected Gram-negative bacteria, establish E. coli Hly as a factor regulating MC effector functions, and argue further for a role of human MCs in innate immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by the Deutsche Forschungsgemeinschaft (SFB621-A8 to S.C.B.).

² S.K. and G.S. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Stephan C. Bischoff, Department of Nutritional Medicine and Immunology, University of Hohenheim, Fruwirthstrasse 12, D-70593 Stuttgart, Germany. E-mail address: bischoff.stephan{at}uni-hohenheim.de

⁴ Abbreviations used in this paper: MC, mast cell; sLT, sulfido-leukotriene; Hly, hemolysin; PKC, protein kinase C; Ec, E. coli; SLO, streptococcal exotoxin streptolysin O; PFT, pore-forming toxin; SCF, stem cell factor; MOI, multiplicity of infection; Isc, short-circuit current; PKC, protein kinase C; PFT, pore-forming toxin; WT, wild type.