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Infection and Immunity, September 2007, p. 4326-4333, Vol. 75, No. 9
0019-9567/07/$08.00+0     doi:10.1128/IAI.00455-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Protease-Activated Receptor 2 Mediates Human Beta-Defensin 2 and CC Chemokine Ligand 20 mRNA Expression in Response to Proteases Secreted by Porphyromonas gingivalis{triangledown}

Henrik Dommisch,1,2* Whasun O. Chung,1 Maryam G. Rohani,1 David Williams,6 Minnie Rangarajan,7 Mike A. Curtis,7 and Beverly A. Dale1,3,4,5

Departments of Oral Biology,1 Periodontics,3 Biochemistry,4 Medicine/Dermatology, University of Washington, Seattle, Washington,5 Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany,2 Faculty of Medicine, Health and Life Sciences, University of Southampton, Southampton SO16 7PX, United Kingdom,6 Centre for Infectious Disease, Institute of Cell and Molecular Science, Barts and the London, Queen Mary, London E1 2AT, United Kingdom7

Received 28 March 2007/ Returned for modification 21 May 2007/ Accepted 12 June 2007

The oral pathogen Porphyromonas gingivalis secretes proteases such as Arg-gingipain B (RgpB) that activate protease-activated receptors (PARs). Human beta-defensins (hBDs) and the macrophage inflammatory protein 3{alpha}/CC chemokine ligand 20 (CCL20) produced by epithelial cells are antimicrobial peptides that provide cytokine function and play an important role in innate immunity. The aim of the present study was to determine whether specific members of the PAR family mediate the expression of these innate immunity markers in gingival epithelial cells (GECs) when exposed to P. gingivalis cell-free culture supernatant or purified RgpB. hBD-2 mRNA in GECs was induced in response to supernatant and purified RgpB from P. gingivalis (P = 0.02 and P = 0.016, respectively). This effect was abrogated by the protease inhibitor tosyl-L-lysine chloromethyl ketone (TLCK) (P < 0.05). In response to P. gingivalis supernatant and to purified RgpB, the hBD-2 mRNA expression was significantly decreased in PAR-2 gene knockdown cells, whereas no change was detected in PAR-1 gene knockdown cells. CCL20 mRNA expression also increased in response to the supernatant of P. gingivalis, and this effect was blocked by the protease inhibitor, TLCK (P = 0.05 and P = 0.024, respectively), and was blocked in PAR-2 gene knockdown cells. Our data indicate that hBD-2 and CCL20 mRNA up-regulation by P. gingivalis supernatant and purified RgpB was mediated via PAR-2, but not via PAR-1, and that proteases play a role in the regulation of innate immune responses in GECs. GECs use PARs to recognize P. gingivalis and mediate cell responses involved in innate immunity.

* Corresponding author. Mailing address: Department of Oral Biology, School of Dentistry, University of Washington, Box 357132, Seattle, WA 98195-7132. Phone: (206) 543-1595. Fax: (206) 685-3162. E-mail: hd2{at}u.washington.edu

{triangledown} Published ahead of print on 25 June 2007.

Editor: R. P. Morrison

Infection and Immunity, September 2007, p. 4326-4333, Vol. 75, No. 9
0019-9567/07/$08.00+0     doi:10.1128/IAI.00455-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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