Clostridium difficile toxins A and B directly stimulate human mast cells

Gesa K A Meyer, Anne Neetz, Gudrun Brandes, Dimitrios Tsikas, Joseph H. Butterfield, Ingo Just, Ralf Gerhard

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)3868-3876
Number of pages9
JournalInfection and Immunity
Volume75
Issue number8
DOIs
StatePublished - Aug 2007

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Mast Cells
rho GTP-Binding Proteins
p38 Mitogen-Activated Protein Kinases
Actin Cytoskeleton
Pseudomembranous Enterocolitis
Hexosaminidases
Prostaglandin D2
Cell Line
Mitogen-Activated Protein Kinase 3
Clostridium difficile
Mitogen-Activated Protein Kinase 1
Interleukin-8
Dinoprostone
Prostaglandins
Clostridium difficile toxB protein
Clostridium difficile tcdA protein
Actins
Signal Transduction
Cell Count
Electrons

ASJC Scopus subject areas

  • Immunology

Cite this

Meyer, G. K. A., Neetz, A., Brandes, G., Tsikas, D., Butterfield, J. H., Just, I., & Gerhard, R. (2007). Clostridium difficile toxins A and B directly stimulate human mast cells. Infection and Immunity, 75(8), 3868-3876. https://doi.org/10.1128/IAI.00195-07

Clostridium difficile toxins A and B directly stimulate human mast cells. / Meyer, Gesa K A; Neetz, Anne; Brandes, Gudrun; Tsikas, Dimitrios; Butterfield, Joseph H.; Just, Ingo; Gerhard, Ralf.

In: Infection and Immunity, Vol. 75, No. 8, 08.2007, p. 3868-3876.

Research output: Contribution to journalArticle

Meyer, GKA, Neetz, A, Brandes, G, Tsikas, D, Butterfield, JH, Just, I & Gerhard, R 2007, 'Clostridium difficile toxins A and B directly stimulate human mast cells', Infection and Immunity, vol. 75, no. 8, pp. 3868-3876. https://doi.org/10.1128/IAI.00195-07
Meyer GKA, Neetz A, Brandes G, Tsikas D, Butterfield JH, Just I et al. Clostridium difficile toxins A and B directly stimulate human mast cells. Infection and Immunity. 2007 Aug;75(8):3868-3876. https://doi.org/10.1128/IAI.00195-07
Meyer, Gesa K A ; Neetz, Anne ; Brandes, Gudrun ; Tsikas, Dimitrios ; Butterfield, Joseph H. ; Just, Ingo ; Gerhard, Ralf. / Clostridium difficile toxins A and B directly stimulate human mast cells. In: Infection and Immunity. 2007 ; Vol. 75, No. 8. pp. 3868-3876.
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