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J Med Microbiol 57 (2008), 500-507; DOI: 10.1099/jmm.0.47679-0
© 2008 Society for General Microbiology
ISSN 1473-5644

Dual regulation of interleukin-8 production in human oral epithelial cells upon stimulation with gingipains from Porphyromonas gingivalis

Akiko Uehara1, Mariko Naito2, Takahisa Imamura3, Jan Potempa4,5, James Travis5, Koji Nakayama2 and Haruhiko Takada1

1 Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, Sendai, Japan

2 Division of Microbiology and Oral Infection, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

3 Division of Molecular Pathology, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan

4 Department of Microbiology, Faculty of Biotechnology, Jagiellonian University, Kraków, Poland

5 Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA, USA

Correspondence
Akiko Uehara
kyoro{at}mail.tains.tohoku.ac.jp

Received 8 October 2007
Accepted 19 December 2007

Cysteine proteinases from Porphyromonas gingivalis, or gingipains, are considered to be key virulence factors of the bacterium in relation to periodontal diseases. Incubation of human oral epithelial cells with lysine-specific gingipain (Kgp) and high-molecular-mass arginine-specific gingipain (HRgpA) resulted in a decrease in the production of interleukin (IL)-8, but not in the production of other pro-inflammatory cytokines. In contrast, arginine-specific gingipain 2 (RgpB) increased IL-8 production. RNA interference assays demonstrated that Kgp- and HRgpA-mediated downregulation and RgpB-mediated upregulation occurred through protease-activated receptor (PAR)-1 and PAR-2 signalling. Although the RgpB-mediated upregulation of IL-8 production occurred through nuclear factor-kappa B (NF-{kappa}B), the Kgp- and HRgpA-mediated downregulation was not negated in NF-{kappa}B-silenced cells. Both the haemagglutinin and the enzymic domains are required for Kgp and HRgpA to downregulate the production of IL-8 in human oral epithelial cells, and the two domains are thought to co-exist. These results suggest that gingipains preferentially suppress IL-8, resulting in attenuation of the cellular recognition of bacteria, and as a consequence, sustain chronic inflammation.

Abbreviations: FPR-cmk, Phe-Pro-Arg-chloromethyl ketone; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HRgpA, high-molecular-mass arginine-specific gingipain; IFN-{gamma}, gamma interferon; IL, interleukin; Kgp, lysine-specific gingipain; NF-{kappa}B, nuclear factor-kappa B; PAR, protease-activated receptor; Rgp, arginine-specific gingipain; PAR-1AP, PAR-1 agonist peptide; PAR-2AP, PAR-2 agonist peptide; PAR-3AP, PAR-3 agonist peptide; siRNA, short interfering RNA; z-FKck, benzyloxycarbonyl-Phe-Lys-chloromethyl; TNF-{alpha}, tumour necrosis factor alpha.






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