Induction of apoptosis in human gingival fibroblasts by a Porphyromonas gingivalis protease preparation

Wang, Pao-Li; Shirasu, Shinya; Shinohara, Mitsuko; Daito, Michiharu; Oido, Mari; Kowashi, Yusuke; Ohura, Kiyoshi

doi:10.1016/s0003-9969(99)00002-3

Cited by 44 publications

(43 citation statements)

References 27 publications

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“…19,[48][49][50] P. gingivalis has been shown to promote cell death in KB cells as well as in gingival fibroblasts. 51,52 Our data suggest that P. gingivalis does not promote cell death in HCAEC (unpublished observations). However, purified gingipains, major extracellular and cell-associated proteinases, from P. gingivalis have been shown to induce apoptosis of endothelial cells.…”

Section: Bacterial Persistence and Host Cell Survivalmentioning

confidence: 59%

Autophagy: A Highway for Porphyromonas gingivalis in Endothelial Cells

Bélanger

Rodrigues²,

Dunn³

et al. 2006

Autophagy

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Section: Bacterial Persistence and Host Cell Survivalmentioning

confidence: 59%

Autophagy: A Highway for Porphyromonas gingivalis in Endothelial Cells

Bélanger

Rodrigues²,

Dunn³

et al. 2006

Autophagy

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“…Previous studies have indicated that P. gingivalis induces apoptosis in Jurkat T cells, B cells, and human gingival fibroblasts yet inhibits apoptosis in human monocytes, macrophages and neutrophils (15,18,31,35,42). In particular, a recent study on the apoptotic responses of primary GECs infected with P. gingivalis demonstrated that prolonged bacterial invasion upregulates expression of the antiapoptotic protein Bcl-2 and downregulates that of the proapoptotic Bax protein.…”

Section: Discussionmentioning

confidence: 99%

Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway Contributes to Survival of Primary Epithelial Cells Infected with the Periodontal Pathogen Porphyromonas gingivalis

et al. 2004

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Porphyromonas gingivalis, an important periodontal pathogen, infects primary gingival epithelial cells (GECs). Despite the large number of bacteria that replicate inside the GECs, the host cell remains viable. We demonstrate that P. gingivalis triggers rapid and reversible surface phosphatidylserine exposure through a mechanism requiring caspase activation. However, after 1 day of infection, the bacteria no longer induce phosphatidylserine externalization and instead protect infected cells against apoptosis. Infection exerts its effect at the level of mitochondria, as P. gingivalis also blocks depolarization of the mitochondrial transmembrane potential and cytochrome c release. Interestingly, protein kinase B/Akt is phosphorylated during infection, which can be blocked with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. Suppression of the PI3K/Akt pathway following staurosporine treatment results in mitochondrial-membrane depolarization, cytochrome c release, DNA fragmentation, and increased apoptosis of infected GECs. Thus, P. gingivalis stimulates early surface exposure of phosphatidylserine, which could downmodulate the inflammatory response, while also promoting host cell survival through the PI3K/Akt pathway.

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“…Butyric acid, as well as other volatile fatty acids released as byproducts of anaerobic metabolism by P. gingivalis, are known to induce apoptosis (22) and are likely candidates for the heat-stable factors in culture supernatant reported to cause lymphocyte apoptosis (15). Significantly increased apoptosis has also been observed in both epithelial cells and human gingival fibroblasts exposed to active P. gingivalis protease preparations (3,39), although in the latter case, this did not occur when the protease was inactivated. The similar responses with both active and TLCK-treated HRpgA in the present study indicate that the action of this molecule is independent of its proteolytic activity, and it is thus unlikely to be operating via activation of protease-activated receptors on epithelial cells (27).…”

Section: Discussionmentioning

confidence: 99%

Nuclear Targeting ofPorphyromonas gingivalisW50 Protease in Epithelial Cells

Scragg¹,

Alsam²,

Rangarajan

et al. 2002

Infect Immun

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Porphyromonas gingivalis is an important pathogen associated with destructive periodontal disease and is able to invade the epithelial cell barrier. Its cysteine proteases are recognized as major virulence factors, and in this study, we examined the interaction of the arginine-specific protease with epithelial cells in culture. Three cell lines (KB, HeLa, and SCC4) were incubated with strain W50 culture supernatant; stained with monoclonal antibody 1A1, which recognizes an epitope on the adhesin (␤) component of the cysteine protease-adhesin (␣/␤) heterodimer; and viewed using immunofluorescence microscopy. Within 1 h, the protease traversed the plasma membrane and was localized around the nucleus before becoming concentrated in the cytoplasm after 24 to 48 h. In contrast, the purified arginine-specific heterodimeric protease (HRgpA) rapidly entered the nucleus within 15 to 30 min. This nuclear targeting (i) was seen with active and N␣-p-tosyl-L-lysine chloromethyl ketone (TLCK)-inactivated HRgpA, indicating it was independent of the proteolytic activity; (ii) occurred at both 4 and 37°C; and (iii) failed to occur with the monomeric protease (RgpA cat ), indicating the importance of the adhesin chain of the HRgpA protease to this process. Rapid cell entry was also observed with recombinant catalytic (␣) and adhesin (␤) chains, with the latter again targeting the nuclear area. After 48 h of incubation with HRgpA, significant dose-dependent stimulation of metabolic activity was observed (measured by reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide), and a doubling of mitotic activity combined with the presence of apoptotic cells indicated that HRgpA may interfere with cell cycle control mechanisms. These effects were seen with both active and TLCK-inactivated protease, confirming that they were not dependent on proteolytic activity, and thus provide new insights into the functioning of this P. gingivalis protease.Periodontal diseases are chronic inflammatory conditions resulting from the host response to microbial challenge and are characterized by the formation of deepening periodontal pockets and the destruction of both hard and soft tissues supporting the teeth. An essential step in initiating any infection involves adherence to, and/or invasion of, host cells by pathogens or their products. As epithelial cells form the first barrier to invasion by bacteria which colonize the gingival crevice, the nature of their interaction with potential pathogens is likely to have a major influence on the progression of disease.Porphyromonas gingivalis is an anaerobic gram-negative bacterium important in destructive periodontal disease whose main ecological niche is the subgingival crevice adjacent to the tooth surface and the epithelial attachment apparatus of the soft tissues. The organism can invade gingival tissue in advanced periodontitis (18) and can be taken up by gingival and pocket epithelial cells, oral epithelial cell lines, and endothelial cells in vitro (13,23,33,40). The nature of the ...

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Induction of apoptosis in human gingival fibroblasts by a Porphyromonas gingivalis protease preparation

Cited by 44 publications

References 27 publications

Autophagy: A Highway for Porphyromonas gingivalis in Endothelial Cells

Autophagy: A Highway for Porphyromonas gingivalis in Endothelial Cells

Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway Contributes to Survival of Primary Epithelial Cells Infected with the Periodontal Pathogen Porphyromonas gingivalis

Nuclear Targeting ofPorphyromonas gingivalisW50 Protease in Epithelial Cells

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