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Infection and Immunity, August 2007, p. 3868-3876, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00195-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Clostridium difficile Toxins A and B Directly Stimulate Human Mast Cells{triangledown}

Gesa K. A. Meyer,1 Anne Neetz,1 Gudrun Brandes,2 Dimitrios Tsikas,3 Joseph H. Butterfield,4 Ingo Just,1 and Ralf Gerhard1*

Department of Toxicology, Hannover Medical School, 30625 Hannover, Germany,1 Department of Cell Biology in the Center of Anatomy, Hannover Medical School, 30625 Hannover, Germany,2 Department of Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany,3 Divisions of Allergic Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota4

Received 6 February 2007/ Returned for modification 23 February 2007/ Accepted 7 May 2007

Clostridium difficile toxins A and B (TcdA and TcdB) are the causative agents of 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 the activation of proinflammatory signal pathways. TcdA and TcdB inactivate Rho GTPases, the master regulators of the actin cytoskeleton. The inactivation of Rho GTPases induced a reorganization of the actin cytoskeleton accompanied by morphological changes of cells. The TcdB-induced reorganization of the actin cytoskeleton in HMC-1 cells reduced the number of electron-dense mast cell-specific granules. Accordingly, TcdB induced the release of hexosaminidase, a marker for degranulation, in HMC-1 cells. The actin rearrangement was found to be responsible for degranulation since latrunculin B induced a comparable hexosaminidase release. In addition, TcdB as well as latrunculin B induced the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 and also resulted in a p38 MAPK-dependent increased formation of prostaglandins D2 and E2. The autocrine stimulation of HMC-1 cells by prostaglandins partially contributed to the degranulation. Interestingly, TcdB-treated HMC-1 cells, but not latrunculin B-treated HMC-1 cells, showed a strong p38 MAPK-dependent increase in interleukin-8 release. Differences in the mast cell responses to TcdB and latrunculin B are probably due to the presence of functionally inactive Rho GTPases in toxin-treated cells. Thus, the HMC-1 cell line is a promising model for studying the direct effects of C. difficile toxins on mast cells independently of the tissue context.

* Corresponding author. Mailing address: Department of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. Phone: 49 511 532-2810. Fax: 49 511 532-2879. E-mail: gerhard.ralf{at}mh-hannover.de

{triangledown} Published ahead of print on 21 May 2007.

Editor: D. L. Burns

Infection and Immunity, August 2007, p. 3868-3876, Vol. 75, No. 8
0019-9567/07/$08.00+0     doi:10.1128/IAI.00195-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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