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Infection and Immunity, December 2008, p. 5514-5523, Vol. 76, No. 12
0019-9567/08/$08.00+0 doi:10.1128/IAI.00625-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
Porphyromonas gingivalis, Gamma Interferon, and a Proapoptotic Fibronectin Matrix Form a Synergistic Trio That Induces c-Jun N-Terminal Kinase 1-Mediated Nitric Oxide Generation and Cell Death
Abhijit Ghosh,1
Ji Young Park,1
Christopher Fenno,2 and
Yvonne L. Kapila1*
Departments of Periodontics and Oral Medicine,1 Biologic and Material Sciences, University of Michigan, School of Dentistry, Ann Arbor, Michigan 481092
Received 21 May 2008/ Returned for modification 16 July 2008/ Accepted 26 September 2008
During infection and inflammation, bacterial and inflammatory proteases break down extracellular matrices into macromolecular fragments. Fibronectin fragments are associated with disease severity in arthritis and periodontitis. The mechanisms by which these fragments contribute to disease pathogenesis are unclear. One likely mechanism is that fibronectin fragments induce apoptosis of resident cells, which can be further modulated by nitric oxide. Nitric oxide levels are increased at inflammatory sites in periodontitis patients. The aim of this study was to examine whether a proapoptotic fibronectin matrix (AFn) exerts its action by inducing nitric oxide and whether priming by bacterial and inflammatory components exacerbates this mechanism. Our data demonstrate that AFn increased the levels of nitric oxide and inducible nitric oxide synthase (iNOS) dose and time dependently in periodontal ligament (PDL) cells. These effects and apoptosis were inhibited by iNOS suppression and enhanced by iNOS overexpression. Nitric oxide and iNOS induction were paralleled by increased c-Jun N-terminal kinase 1 (JNK-1) phosphorylation. JNK-1 overexpression enhanced the expression of nitric oxide and iNOS, whereas inhibiting JNK-1 by small interfering RNA or a kinase mutant reversed these findings. Priming PDL cells with Porphyromonas gingivalis, its lipopolysaccharide (LPS), or gamma interferon (IFN-
) further increased nitric oxide levels and apoptosis. Escherichia coli and Streptococcus mutans induced lesser effects. Gingival fibroblasts and neutrophils responded to a lesser degree to these stimuli, whereas keratinocytes were resistant to apoptosis. Thus, proapoptotic matrices trigger nitric oxide release via JNK-1, promoting further apoptosis in host cells. LPS and IFN- accentuate this mechanism, suggesting that during inflammation, the affected matrices and bacterial and inflammatory components combined exert a greater pathogenic effect on host cells.
* Corresponding author. Mailing address: Department of Periodontics and Oral Medicine, University of Michigan, School of Dentistry, 1011 N. University Ave., Ann Arbor, MI 48109-1078. Phone: (734) 615-2295. Fax: (734) 763-5503. E-mail: ykapila{at}umich.edu
Published ahead of print on 6 October 2008.
Infection and Immunity, December 2008, p. 5514-5523, Vol. 76, No. 12
0019-9567/08/$08.00+0 doi:10.1128/IAI.00625-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.
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