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Infection and Immunity, March 2004, p. 1706-1714, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1706-1714.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Porphyromonas gingivalis Induces Receptor Activator of NF-{kappa}B Ligand Expression in Osteoblasts through the Activator Protein 1 Pathway

Nobuo Okahashi,1* Hiroaki Inaba,1 Ichiro Nakagawa,2 Taihei Yamamura,2 Masae Kuboniwa,3 Koji Nakayama,4 Shigeyuki Hamada,2 and Atsuo Amano1

Departments of Oral Frontier Biology,1 Oral and Molecular Microbiology,2 Preventive Dentistry, Osaka University Graduate School of Dentistry, Osaka-Suita 565-0871,3 Division of Microbiology and Oral Infection, Course of Medical and Dental Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan4

Received 22 August 2003/ Returned for modification 12 November 2003/ Accepted 19 November 2003

Porphyromonas gingivalis, an important periodontal pathogen, is closely associated with inflammatory alveolar bone resorption, and several components of the organism such as lipopolysaccharides have been reported to stimulate production of cytokines that promote inflammatory bone destruction. We investigated the effect of infection with viable P. gingivalis on cytokine production by osteoblasts. Reverse transcription-PCR and real-time PCR analyses revealed that infection with P. gingivalis induced receptor activator of nuclear factor {kappa}B (NF-{kappa}B) ligand (RANKL) mRNA expression in mouse primary osteoblasts. Production of interleukin-6 was also stimulated; however, osteoprotegerin was not. SB20350 (an inhibitor of p38 mitogen-activated protein kinase), PD98059 (an inhibitor of classic mitogen-activated protein kinase kinase, MEK1/2), wortmannin (an inhibitor of phosphatidylinositol 3 kinase), and carbobenzoxyl-leucinyl-leucinyl-leucinal (an inhibitor of NF-{kappa}B) did not prevent the RANKL expression induced by P. gingivalis. Degradation of inhibitor of NF-{kappa}B-alpha was not detectable; however, curcumin, an inhibitor of activator protein 1 (AP-1), prevented the RANKL production induced by P. gingivalis infection. Western blot analysis revealed that phosphorylation of c-Jun, a component of AP-1, occurred in the infected cells, and an analysis of c-Fos binding to an oligonucleotide containing an AP-1 consensus site also demonstrated AP-1 activation in infected osteoblasts. Infection with P. gingivalis KDP136, an isogenic deficient mutant of arginine- and lysine-specific cysteine proteinases, did not stimulate RANKL production. These results suggest that P. gingivalis infection induces RANKL expression in osteoblasts through AP-1 signaling pathways and cysteine proteases of the organism are involved in RANKL production.

* Corresponding author. Mailing address: Department of Oral Frontier Biology, Osaka University Graduate School of Dentistry, 1-8 Yamadaoka, Suita-Osaka 565-0871, Japan. Phone: 81-6-6879-2976. Fax: 81-6-6879-2976. E-mail: okahashi{at}dent.osaka-u.ac.jp.

Editor: J. N. Weiser

Infection and Immunity, March 2004, p. 1706-1714, Vol. 72, No. 3
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.3.1706-1714.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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