This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Stassen, M. Articles by Schmitt, E. Search for Related Content PubMed PubMed Citation Articles by Stassen, M. Articles by Schmitt, E.

 Previous Article  |  Next Article 

Infection and Immunity, November 2003, p. 6171-6177, Vol. 71, No. 11
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.11.6171-6177.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

The Streptococcal Exotoxin Streptolysin O Activates Mast Cells To Produce Tumor Necrosis Factor Alpha by p38 Mitogen-Activated Protein Kinase- and Protein Kinase C-Dependent Pathways

Institute of Immunology,¹ Institute of Medical Microbiology, Johannes Gutenberg University, Mainz,³ GSF-National Research Center for Environment and Health, Institute of Clinical, Molecular Biology and Tumor Genetics, Munich, Germany²

Received 29 August 2002/ Returned for modification 3 December 2002/ Accepted 13 August 2003

Streptolysin O (SLO), a major virulence factor of pyogenic streptococci, binds to cholesterol in the membranes of eukaryotic cells and oligomerizes to form large transmembrane pores. While high toxin doses are rapidly cytocidal, low doses are tolerated because a limited number of lesions can be resealed. Here, we report that at sublethal doses, SLO activates primary murine bone marrow-derived mast cells to degranulate and to rapidly induce or enhance the production of several cytokine mRNAs, including tumor necrosis factor alpha (TNF-). Mast cell-derived TNF- plays an important protective role in murine models of acute inflammation, and the production of this cytokine was analyzed in more detail. Release of biologically active TNF- peaked 4 h after stimulation with SLO. Production of TNF- was blunted upon depletion of protein kinase C by pretreatment of the cells with phorbol-12 myristate-13 acetate. Transient permeabilization of mast cells with SLO also led to the activation of the stress-activated protein kinases p38 mitogen-activated protein (MAP) kinase and c-jun N-terminal kinase (JNK), and inhibition of p38 MAP kinase markedly reduced production of TNF-. In contrast, secretion of preformed granule constituents triggered by membrane permeabilization was not dependent on p38 MAP kinase or on protein kinase C. Thus, transcriptional activation of mast cells following transient permeabilization might contribute to host defense against infections via the beneficial effects of TNF-. However, hyperstimulation of mast cells might also lead to overproduction of TNF-, which would then promote the development of toxic streptococcal syndromes.

Editor: V. J. DiRita

This article has been cited by other articles:

• Kramer, S., Sellge, G., Lorentz, A., Krueger, D., Schemann, M., Feilhauer, K., Gunzer, F., Bischoff, S. C. (2008). Selective Activation of Human Intestinal Mast Cells by Escherichia coli Hemolysin. J. Immunol. 181: 1438-1445 [Abstract] [Full Text]  
• von Kockritz-Blickwede, M., Goldmann, O., Thulin, P., Heinemann, K., Norrby-Teglund, A., Rohde, M., Medina, E. (2008). Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 111: 3070-3080 [Abstract] [Full Text]  
• Klein, M., Klein-Hessling, S., Palmetshofer, A., Serfling, E., Tertilt, C., Bopp, T., Heib, V., Becker, M., Taube, C., Schild, H., Schmitt, E., Stassen, M. (2006). Specific and Redundant Roles for NFAT Transcription Factors in the Expression of Mast Cell-Derived Cytokines. J. Immunol. 177: 6667-6674 [Abstract] [Full Text]  
• Jawdat, D. M., Rowden, G., Marshall, J. S. (2006). Mast Cells Have a Pivotal Role in TNF-Independent Lymph Node Hypertrophy and the Mobilization of Langerhans Cells in Response to Bacterial Peptidoglycan. J. Immunol. 177: 1755-1762 [Abstract] [Full Text]  
• Kirkham, L.-A. S., Kerr, A. R., Douce, G. R., Paterson, G. K., Dilts, D. A., Liu, D.-F., Mitchell, T. J. (2006). Construction and Immunological Characterization of a Novel Nontoxic Protective Pneumolysin Mutant for Use in Future Pneumococcal Vaccines. Infect. Immun. 74: 586-593 [Abstract] [Full Text]  
• Park, J. M., Ng, V. H., Maeda, S., Rest, R. F., Karin, M. (2004). Anthrolysin O and Other Gram-positive Cytolysins Are Toll-like Receptor 4 Agonists. J. Exp. Med. 200: 1647-1655 [Abstract] [Full Text]