Cleavage of protease-activated receptors on an immortalized oral epithelial cell line by Porphyromonas gingivalis gingipains

Giacaman, Rodrigo A.; Asrani, Anil C.; Ross, Kristin; Herzberg, Mark C.

doi:10.1099/mic.0.029132-0

Cited by 49 publications

(48 citation statements)

References 45 publications

(44 reference statements)

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“…Gingipains have been shown to activate PAR2 in immune inflammatory cells and in cells from the oral epithelial barrier, leading to increased production of proinflammatory mediators (4,8,10,(33)(34)(35) and activation of signaling pathways associated with increased inflammatory responses (36). In addition, neutrophil protease 3 was also shown to activate host cells through PAR2, inducing the release of proinflammatory cytokines (6), which not only have a direct effect on periodontal destruction but can also act indirectly by upregulating MMP expression (37,38).…”

Section: Discussionmentioning

confidence: 99%

“…PAR2 activation-associated enhanced biosynthesis of proinflammatory mediators has been well established (4)(5)(6)(7)(8)(9)(10). A previous study by our group demonstrated that PAR2 mediates host cell mechanisms responsible for increased levels of prostaglandin E2, gamma interferon, interleukin-␤ (IL-1␤), and IL-6 and for the resulting increased alveolar bone loss in a periodontitis model of P. gingivalis infection in mice (8).…”

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confidence: 99%

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Periodontal Treatment Downregulates Protease-Activated Receptor 2 in Human Gingival Crevicular Fluid Cells

et al. 2013

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b Protease-activated receptor 2 (PAR2) is implicated in the pathogenesis of chronic inflammatory diseases, including periodontitis; it can be activated by gingipain and produced by Porphyromonas gingivalis and by neutrophil protease 3 (P3). PAR2 activation plays a relevant role in inflammatory processes by inducing the release of important inflammatory mediators associated with periodontal breakdown. The effects of periodontal treatment on PAR2 expression and its association with levels of proinflammatory mediators and activating proteases were investigated in chronic periodontitis patients. Positive staining for PAR2 was observed in gingival crevicular fluid cells and was reflective of tissue destruction. Overexpression of PAR2 was positively associated with inflammatory clinical parameters and with the levels of interleukin-6 (IL-6), IL-8, tumor necrosis factor alpha, matrix metalloprotease 2 (MMP-2), MMP-8, hepatocyte growth factor, and vascular endothelial growth factor. Elevated levels of gingipain and P3 and decreased levels of dentilisin and the protease inhibitors secretory leukocyte protease inhibitor and elafin were also associated with PAR2 overexpression. Healthy periodontal sites from individuals with chronic periodontitis showed diminished expression of PAR2 mRNA and the PAR2 protein (P < 0.05). Furthermore, periodontal treatment resulted in decreased PAR2 expression and correlated with decreased expression of inflammatory mediators and activating proteases. We concluded that periodontal treatment resulted in decreased levels of proteases and that proinflammatory mediators are associated with decreased PAR2 expression, suggesting that PAR2 expression is influenced by the presence of periodontal infection and is not a constitutive characteristic favoring periodontal inflammation.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Periodontal Treatment Downregulates Protease-Activated Receptor 2 in Human Gingival Crevicular Fluid Cells

et al. 2013

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“…Although it has been reported that different mammalian and prokaryotic proteases can activate PARs (e.g., human trypsin [55,56] or Porphyromonas gingivalis gingipains [57]), different forms of these receptors exhibit specificities for various activating proteases (e.g., PAR2 can be activated by trypsin but not by thrombin). Additionally, most studies investigating how microbes disrupt the intestinal epithelium via PAR activation have focused on pathogens.…”

Section: Discussionmentioning

confidence: 99%

Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2

et al. 2015

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e Microbial protease-mediated disruption of the intestinal epithelium is a potential mechanism whereby a dysbiotic enteric microbiota can lead to disease. This mechanism was investigated using the colitogenic, protease-secreting enteric microbe Enterococcus faecalis. Caco-2 and T-84 epithelial cell monolayers and the mouse colonic epithelium were exposed to concentrated conditioned media (CCM) from E. faecalis V583 and E. faecalis lacking the gelatinase gene (gelE). The flux of fluorescein isothiocyanate (FITC)-labeled dextran across monolayers or the mouse epithelium following exposure to CCM from parental or mutant E. faecalis strains indicated paracellular permeability. A protease-activated receptor 2 (PAR2) antagonist and PAR2-deficient (PAR2 ؊/؊ ) mice were used to investigate the role of this receptor in E. faecalis-induced permeability. Gelatinase (GelE) purified from E. faecalis V583 was used to confirm the ability of this protease to induce epithelial cell permeability and activate PAR2. The protease-mediated permeability of colonic epithelia from wild-type (WT) and PAR2 ؊/؊ mice by fecal supernatants from ulcerative colitis patients was assessed. Secreted E. faecalis proteins induced permeability in epithelial cell monolayers, which was reduced in the absence of gelE or by blocking PAR2 activity. Secreted E. faecalis proteins induced permeability in the colonic epithelia of WT mice that was absent in tissues from PAR2 ؊/؊ mice. Purified GelE confirmed the ability of this protease to induce epithelial cell permeability via PAR2 activation. Fecal supernatants from ulcerative colitis patients induced permeability in the colonic epithelia of WT mice that was reduced in tissues from PAR2 ؊/؊ mice. Our investigations demonstrate that GelE from E. faecalis can regulate enteric epithelial permeability via PAR2.A potential mechanism for the pathogenesis of inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS) involves disruption of the intestinal epithelial barrier and exposure of a genetically defective immune system to enteric microbial antigens. Indeed, IBD and IBS patients exhibit a higher level of intestinal permeability than healthy controls (1-7). Additionally, first-degree relatives of IBD patients display elevated levels of enteric permeability (8-10), suggesting that this abnormality is independent of inflammation. Consistent with this hypothesis are animal models of colitis that use chemical disruption of the epithelial barrier with trinitrobenzene sulfonic acid, dextran sodium sulfate, or nonsteroidal anti-inflammatory drugs (NSAIDs) to elicit inflammation (11). Further, disruption of the intestinal epithelial barrier by exposure of susceptible patients to NSAIDs (blockers of prostaglandin synthesis) is a risk factor for intestinal inflammation (12).Enteric proteases can act broadly as catalysts of protein degradation or specifically as selective agents that control physiological processes (13). Additionally, these enzymes can disrupt mucosal barriers and modulate the host immune resp...

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“…In response to L. monocytogenes , epithelial cells release IL-1α and, in an IL-1RI-dependent manner, modulate autonomous resistance to these invasive enteric pathogens. Other invasive mucosal pathogens including C. albicans 23 and Porphyromas gingivalis 25,28,29 also induce the release of IL-1α from oral keratinocytes over time, suggesting that the epithelial response to pathogens could be generalized.…”

Section: Discussionmentioning

confidence: 99%

IL-1 receptor regulates S100A8/A9-dependent keratinocyte resistance to bacterial invasion

et al. 2012

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Previously we reported that epithelial cells respond to exogenous IL-1α by increasing expression of several genes involved in the host response to microbes, including the antimicrobial protein complex calprotectin (S100A8/A9). Given that S100A8/A9 protects epithelial cells against invading bacteria, we studied whether IL-1α augments S100A8/A9-dependent resistance to bacterial invasion of oral keratinocytes. When inoculated with Listeria monocytogenes, human buccal epithelial (TR146) cells expressed and released IL-1α. Subsequently, IL-1α-containing media from Listeria-infected cells increased S100A8/A9 gene expression in naïve TR146 cells an IL-1 receptor (IL-1R)-dependent manner. Incubation with exogenous IL-1α decreased Listeria invasion into TR146 cells, whereas invasion increased with IL-1R antagonist. Conversely, when S100A8/A9 genes were knocked down using shRNA, TR146 cells responded to exogenous IL-1α with increased intracellular bacteria. These data strongly suggest that infected epithelial cells release IL-1α to signal neighboring keratinocytes in a paracrine manner, promoting S100A8/A9-dependent resistance to invasive L. monocytogenes.

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Cleavage of protease-activated receptors on an immortalized oral epithelial cell line by Porphyromonas gingivalis gingipains

Cited by 49 publications

References 45 publications

Periodontal Treatment Downregulates Protease-Activated Receptor 2 in Human Gingival Crevicular Fluid Cells

Periodontal Treatment Downregulates Protease-Activated Receptor 2 in Human Gingival Crevicular Fluid Cells

Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2

IL-1 receptor regulates S100A8/A9-dependent keratinocyte resistance to bacterial invasion

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