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Infection and Immunity, September 2001, p. 5925-5930, Vol. 69, No. 9
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.9.5925-5930.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Recombinant Actinobacillus actinomycetemcomitans Cytolethal Distending Toxin Proteins Are Required To Interact To Inhibit Human Cell Cycle Progression and To Stimulate Human Leukocyte Cytokine Synthesis

Sumio Akifusa,1 Stephen Poole,2 Jo Lewthwaite,1 Brian Henderson,1,* and Sean P. Nair1

Cellular Microbiology Research Group, Eastman Dental Institute, University College London, London WC1X 8LD,1 and Division of Endocrinology, National Institute for Biological Standards and Control, Potters Bar, Herts,2 United Kingdom

Received 27 March 2001/Returned for modification 14 May 2001/Accepted 15 June 2001

It has recently been discovered that Actinobacillus actinomycetemcomitans, an oral bacterium causing periodontitis, produces cytolethal distending toxin (CDT), a cell cycle-modulating toxin that has three protein subunits: CdtA, CdtB, and CdtC. In this study, we have cloned and expressed each toxin gene from A. actinomycetemcomitans in Escherichia coli and purified the recombinant Cdt proteins to homogeneity. Individual Cdt proteins failed to induce cell cycle arrest of the human epithelial cell line HEp-2. The only combinations of toxin proteins causing cell cycle arrest were the presence of all three Cdt proteins and the combination of CdtB and CdtC. A similar experimental protocol was used to determine if recombinant Cdt proteins were able to induce human peripheral blood mononuclear cells (PBMCs) to produce cytokines. The individual Cdt proteins were able to induce the synthesis by PBMCs of interleukin-1beta (IL-1beta ), IL-6, and IL-8 but not of tumor necrosis factor alpha, IL-12, or granulocyte-macrophage colony-stimulating factor, with CdtC being the most potent and CdtB being the least potent cytokine inducer. There was evidence of synergism between these Cdt proteins in the stimulation of cytokine production, most markedly with gamma interferon, which required the minimum interaction of CdtB and -C to stimulate production.

* Corresponding author. Mailing address: Cellular Microbiology Research Group, Eastman Dental Institute, University College London, 256 Gray's Inn Rd., London WC1X 8LD, United Kingdom. Phone: 44 2079151190. Fax: 44 2079151190. E-mail: b.henderson{at}eastman.ucl.ac.uk.

Infection and Immunity, September 2001, p. 5925-5930, Vol. 69, No. 9
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.9.5925-5930.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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