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Infection and Immunity, August 2001, p. 5121-5130, Vol. 69, No. 8
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.8.5121-5130.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Arginine-Specific Protease from Porphyromonas gingivalis Activates Protease-Activated Receptors on Human Oral Epithelial Cells and Induces Interleukin-6 Secretion

Afrodite Lourbakos,1 Jan Potempa,2 James Travis,3 Michael R. D'Andrea,4 Patricia Andrade-Gordon,4 Rosemary Santulli,4 Eleanor J. Mackie,5 and Robert N. Pike1,*

Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria 3800,1 and School of Veterinary Science, University of Melbourne, Parkville, Victoria 3010,5 Australia; Department of Microbiology and Immunology, Jagiellonian University, Cracow, Poland2; Department of Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia 306023; and Drug Discovery, The R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 194774

Received 18 December 2000/Returned for modification 14 February 2001/Accepted 7 May 2001

Periodontitis is a chronic inflammatory disease affecting oral tissues. Oral epithelial cells represent the primary barrier against bacteria causing the disease. We examined the responses of such cells to an arginine-specific cysteine proteinase (RgpB) produced by a causative agent of periodontal disease, Porphyromonas gingivalis. This protease caused an intracellular calcium transient in an oral epithelial cell line (KB), which was dependent on its enzymatic activity. Since protease-activated receptors (PARs) might mediate such signaling, reverse transcription-PCR was used to characterize the range of these receptors expressed in the KB cells. The cells were found to express PAR-1, PAR-2, and PAR-3, but not PAR-4. In immunohistochemical studies, human gingival epithelial cells were found to express PAR-1, PAR-2, and PAR-3 on their surface, but not PAR-4, indicating that the cell line was an effective model for the in vivo situation. PAR-1 and PAR-2 expression was confirmed in intracellular calcium mobilization assays by treatment of the cells with the relevant receptor agonist peptides. Desensitization experiments strongly indicated that signaling of the effects of RgpB was occurring through PAR-1 and PAR-2. Studies with cells individually transfected with each of these two receptors confirmed that they were both activated by RgpB. Finally, it was shown that, in the oral epithelial cell line, PAR activation by the bacterial protease-stimulated secretion of interleukin-6. This induction of a powerful proinflammatory cytokine suggests a mechanism whereby cysteine proteases from P. gingivalis might mediate inflammatory events associated with periodontal disease on first contact with a primary barrier of cells.

* Corresponding author. Mailing address: Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria 3800, Australia. Phone: 61-3-99053923. Fax: 61-3-99054699. E-mail rob.pike{at}med.monash.edu.au.

Infection and Immunity, August 2001, p. 5121-5130, Vol. 69, No. 8
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.8.5121-5130.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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