Local Chemokine Paralysis, a Novel Pathogenic Mechanism for<i>Porphyromonas gingivalis</i>

Darveau, Richard P.; Belton, Carol M.; Reife, Robert A.; Lamont, Richard J.

doi:10.1128/iai.66.4.1660-1665.1998

Cited by 330 publications

(240 citation statements)

References 42 publications

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“…Cytokines that are secreted into the cell culture medium in response to P. gingivalis have previously been shown to be degraded by these proteases, which prevents autocrine cytokine responses. [41][42][43] Indeed, the presence of nine lysine and five arginine residues in IL-36c would likely make the cytokine highly susceptible to degradation by P. gingivalis proteases. This raises the possibility that P. gingivalis might be able to dysregulate the stimulation of IL-23p19 and EBI3 expression by autocrine IL-36c signaling.…”

Section: Discussionmentioning

confidence: 99%

MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

et al. 2018

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Interleukin (IL)-36 cytokines are important regulators of mucosal homeostasis and inflammation. We previously established that oral epithelial cells strongly upregulate IL-36γ expression in response to the bacterial pathogen Porphyromonas gingivalis. Here, we have established that IL-36γ stimulates the expression of the IL-12 cytokine family members, IL-23p19 and Epstein-Barr Virus-Induced Gene 3 (EBI3), by oral epithelial cells; their expression was also selectively stimulated by IL-36α. Notably, IL-23p19 and EBI3 expression was not stimulated by P. gingivalis, thus suggesting that their expression by the oral epithelium in response to P. gingivalis is likely to be mediated in an autocrine manner by IL-36γ. The IL-36γ-inducible expression of IL-23p19 and EBI3 was found to be diametrically regulated by the mitogen-activated protein kinase/extracellular signal regulated kinase (MEK)-extracellular signal-regulated kinase 1/2 (ERK1/2) pathway, whereby the activation of MEK-ERK signaling likely functions as a negative feedback mechanism to limit EBI3 expression. Furthermore, epidermal growth factor receptor (EGFR) signaling, which is important for mucosal homeostasis, was demonstrated to modulate, in a MEK-ERK-dependent manner, the stimulation of IL-23p19 and EBI3 expression by IL-36γ. IL-23p19 and EBI3 have recently been shown to heterodimerize to form the novel cytokine IL-39 and promote neutrophil expansion. EBI3 has been shown to also have IL-12 cytokine family independent functions (e.g. mediating IL-6 trans-signaling). Thus, this study not only advances our understanding of how IL-36 cytokines may control mucosal inflammation, but also establishes EGFR signaling as a potentially important modulator of IL-36 cytokine function.

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Section: Discussionmentioning

confidence: 99%

MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

et al. 2018

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“…Our previous results [4,13] and laboratory observations show that exposure of GECs to P. gingivalis for up to 48 h, at a multiplicity of infection (MOI) ranging from 10 to 1000, does not a¡ect epithelial cell viability as evidenced by intracellular hydrolysis of calcein-acetomethyl ester and physiologic intracellular calcium ion concentrations. These qualitative viability observations were quantitated with regard to apoptotic cell death by a cell death detection ELI-SA ( Fig.…”

Section: Gec Apoptosismentioning

confidence: 92%

Inhibition of epithelial cell apoptosis by Porphyromonas gingivalis

Nakhjiri

2001

FEMS Microbiology Letters

113

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Porphyromonas gingivalis is periodontal pathogen that is capable of invading gingival epithelial cells (GECs). Apoptotic responses of primary cultures of GECs to P. gingivalis were investigated with a DNA fragmentation ELISA assay. P. gingivalis induced a transient increase in GEC DNA fragmentation; however, after prolonged incubation GECs did not undergo apoptosis. Furthermore, P. gingivalis blocked apoptosis in GECs following stimulation with camptothecin. Immunoblotting of GECs with Bcl-2 or Bax antibodies showed that P. gingivalis up-regulated Bcl-2 levels in GECs, whereas Bax levels were transiently elevated and declined after 24 h stimulation. Streptococcus gordonii did not affect levels of either molecule. RT-PCR demonstrated that induction of Bcl-2 occurs at the transcriptional level. The results suggest that P. gingivalis can inhibit apoptosis in GECs by up-regulation of the anti-apoptotic molecule Bcl-2. The prevention of host cell apoptosis may represent a strategy for P. gingivalis survival within invaded GECs. ß

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“…Important representative examples of these abilities are its capacity to degrade human defensins (Carlisle et al, 2009), its resistance to oxidative burstkilling by polymorphonuclear neutrophils (PMNs) (Mydel et al, 2006) and its ability to inhibit 'at will' the production of crucial proinflammatory cytokines (Bostanci et al, 2007a, b). Although P. gingivalis has the capacity to stimulate interleukin (IL)-8 production by epithelial cells (Sandros et al, 2000;Asai et al, 2001;Kusumoto et al, 2004), it can also inhibit IL-8 production, resulting in hindered PMN chemotaxis, a phenomenon known as 'chemokine paralysis' (Darveau et al, 1998). Porphyromonas gingivalis thereby incapacitates the first line of defence in the periodontal tissues.…”

Section: Survival Strategies Of P Gingivalismentioning

confidence: 99%

Porphyromonas gingivalis: an invasive and evasive opportunistic oral pathogen

Bostancı

Belibasakis

2012

FEMS Microbiol Lett

462

413

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Porphyromonas gingivalis is a Gram-negative oral anaerobe that is involved in the pathogenesis of periodontitis, an inflammatory disease that destroys the tissues supporting the tooth, eventually leading to tooth loss. Porphyromonas gingivalis has can locally invade periodontal tissues and evade the host defence mechanisms. In doing so, it utilizes a panel of virulence factors that cause deregulation of the innate immune and inflammatory responses. The present review discusses the invasive and evasive strategies of P. gingivalis and the role of its major virulence factors in these, namely lipopolysaccharide, capsule, gingipains and fimbriae. Moreover, the role of P. gingivalis as a 'keystone' biofilm species in orchestrating a host response, is highlighted.

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Local Chemokine Paralysis, a Novel Pathogenic Mechanism forPorphyromonas gingivalis

Cited by 330 publications

References 42 publications

MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

MEK‐ERK signaling diametrically controls the stimulation of IL‐23p19 and EBI3 expression in epithelial cells by IL‐36γ

Inhibition of epithelial cell apoptosis by Porphyromonas gingivalis

Porphyromonas gingivalis: an invasive and evasive opportunistic oral pathogen

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