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Down-regulation of interleukin-16 in human mast cells HMC-1 by Clostridium difficile toxins A and B

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Abstract

Toxin A (TcdA) and toxin B (TcdB) are the major virulence factors of Clostridium difficile and are the causative agents for clinical symptoms, such as secretory diarrhoea and pseudomembranous colitis. Mast cells are essentially involved in the toxin-induced colonic inflammatory processes. To study the direct effects of these toxins on the expression of inflammatory genes, a DNA microarray containing evaluated probes of 90 selected inflammatory genes was applied to the immature mast cell line HMC-1. TcdA and TcdB induced up-regulation of only a limited number of genes within the early phase of cell treatment. Interleukin-8 (IL-8), transcription factor c-jun and heme oxygenase-1 messenger RNA (mRNA) increased more than 2-fold. In contrast, IL-16, known as a CD4+ T-cell chemoattractant factor and the chemokine receptor cKit were down-regulated. Stimulation of HMC-1 cells with IL-8 had no effect on IL-16 mRNA level, indicating that both cytokines were independently affected by the toxins. Regulation of both cytokines, however, depended on glucosylation of Rho GTPases as tested by application of enzyme-deficient TcdA or TcdB. Down-regulation of total and secreted IL-16 protein was checked by enzyme-linked immunosorbent assay. The data implicate that TcdA and TcdB affect lymphocyte migration by modulating release of the chemoattractant factor IL-16 from mast cells. In addition, this is the first report showing that Rho GTPases are involved in the regulation of IL-16 expression.

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Acknowledgements

This study was funded by the Deutsche Forschungsgemeinschaft (SFB621, project B5).

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Authors and Affiliations

  1. Institut für Toxikologie, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Ralf Gerhard, Swenja Queißer, Helma Tatge, Gesa Meyer & Ingo Just

  2. Institute of Physiological Chemistry, Hannover Medical School, Hannover, Germany

    Oliver Dittrich-Breiholz

  3. Rudolf-Buchheim-Institute of Pharmacology, Justus-Liebig-Universität, Gießen, Germany

    Michael Kracht

  4. Cummings School of Veterinary Medicine, Tufts University, Medford, MA, USA

    Hanping Feng

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  1. Ralf Gerhard
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  2. Swenja Queißer
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  3. Helma Tatge
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  4. Gesa Meyer
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  5. Oliver Dittrich-Breiholz
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  6. Michael Kracht
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  7. Hanping Feng
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  8. Ingo Just
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Correspondence to Ralf Gerhard.

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Gerhard, R., Queißer, S., Tatge, H. et al. Down-regulation of interleukin-16 in human mast cells HMC-1 by Clostridium difficile toxins A and B. Naunyn-Schmied Arch Pharmacol 383, 285–295 (2011). https://doi.org/10.1007/s00210-010-0592-8

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  • DOI: https://doi.org/10.1007/s00210-010-0592-8

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