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Infect. Immun. doi:10.1128/IAI.00195-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

CLOSTRIDIUM DIFFICILE TOXIN A AND B DIRECTLY STIMULATE HUMAN MAST CELLS

Department of Toxicology, Hannover Medical School, 30625 Hannover, Germany; Department of Cell Biology in the Center of Anatomy, Hannover Medical School, 30625 Hannover, Germany; Department of Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany; Divisions of Allergic Diseases and Internal Medicine, Mayo Clinic, Rochester, MN, USA

^* To whom correspondence should be addressed. Email: gerhard.ralf{at}mh-hannover.de.

	Abstract

Clostridium difficile toxins A and B (TcdA, TcdB) are the causative agents of the antibiotic-associated pseudomembranous colitis. Mucosal mast cells play a crucial role in the inflammatory processes underlying this disease. We studied the direct effects of TcdA and TcdB on the human mast cell line HMC-1 with respect to degranulation, cytokine release and activation of pro-inflammatory signal pathways. TcdA and TcdB inactivate Rho-GTPases, the master regulators of the actin cytoskeleton. Inactivation of Rho GTPases induced a reorganization of the actin cytoskeleton accompanied by morphological changes of cells. The TcdB-induced re-organization of the actin cytoskeleton in HMC-1 reduced the number of electron-dense mast cell specific granules. Accordingly, TcdB induced release of hexosaminidase, a marker for degranulation, in HMC-1. The actin rearrangement was found to be responsible for degranulation since latrunculin B induced comparable hexosaminidase release. In addition, TcdB as well as latrunculin B induced activation of p38 MAPK and ERK1/2 and also resulted in a p38 MAPK-dependent increased formation of prostaglandin D₂ and E₂. The autocrine stimulation of HMC-1 by prostaglandins partially contributed to degranulation. Interestingly, TcdB- but not latrunculin B-treated HMC-1 showed a p38 MAPK-dependent strong increase in interleukin-8 release. Differences in the mast cell response to TcdB and latrunculin B are probably due to the presence of functionally inactive Rho-GTPases in toxin-treated cells. Thus, the HMC-1 is a promising model to study the direct effects of C. difficile toxins on mast cells independently of the tissue context.