Abstract
The tissue destruction that characterizes periodontitis is driven by the host response to bacterial pathogens. Inhibition of glycogen synthase kinase 3β (GSK3β) in innate cells leads to suppression of Toll-like receptor (TLR)-initiated proinflammatory cytokines under nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 transcriptional control and promotion of cyclic adenosine monophosphate response element-binding (CREB)-dependent gene activation. Therefore, we hypothesized that the cell permeable GSK3-specific inhibitor, SB216763, would protect against alveolar bone loss induced by the key periodontal pathogen, Porphyromonas gingivalis (P. gingivalis), in a murine model. B6129SF2/J mice either were infected orally with P. gingivalis ATCC 33277; or treated with SB216763 and infected with P. gingivalis; sham infected; or exposed to vehicle only (dimethyl sulfoxide [DMSO]); or to GSK3 inhibitor only (SB216763). Alveolar bone loss and local (neutrophil infiltration and interleukin [IL]-17) and systemic (tumor necrosis factor [TNF], IL-6, Il-1β and IL-12/IL-23 p40) inflammatory indices also were monitored. SB216763 unequivocally abrogated mean P. gingivalis-induced bone resorption, measured at 14 predetermined points on the molars of defleshed maxillae as the distance from the cementoenamel junction to the alveolar bone crest (p < 0.05). The systemic cytokine response, the local neutrophil infiltration and the IL-17 expression were suppressed (p < 0.001). These data confirm the relevance of prior in vitro phenomena and establish GSK3 as a novel, efficacious therapeutic preventing periodontal disease progression in a susceptible host. These findings also may have relevance to other chronic inflammatory diseases and the systemic sequelae associated with periodontal infections.
Highlights
Periodontitis is a highly prevalent chronic inflammatory disease defined by irreversible destruction of the hard and soft tissues surrounding the teeth
glycogen synthase kinase 3β (GSK3β) is known to be a key mediator of proinflammatory cytokine production during bacterial infections and, subsequently, inhibition of GSK3β leads to an innate hyporeactivity to oral, and other, pathogens
We have shown that GSK3β controls the major immune modulating molecule, IFN-β production in LPS (TLR4)-stimulated human macrophages via a c-Jun and activating transcription factor (ATF)-2-dependent mechanism [7]
Summary
Periodontitis is a highly prevalent chronic inflammatory disease defined by irreversible destruction of the hard and soft tissues surrounding the teeth. GSK3β is a constitutively active serinethreonine kinase that plays a vital role in directing the immune response following TLR stimulation [5]. We have shown that GSK3β controls the major immune modulating molecule, IFN-β production in LPS (TLR4)-stimulated human macrophages via a c-Jun and activating transcription factor (ATF)-2-dependent mechanism [7]. GSK3β negatively regulates production of the endogenous IL-1β antagonist, IL-1R, via its ability to regulate the mitogen-activated protein kinase (MAPK) extracellular-signal-regulated kinase (ERK)1/2 in LPS-stimulated innate cells by a mechanism that involves modulation of the level of inhibitory residue ser on Rac which, subsequently, controls the ability of Rac to activate p21-activated protein kinase [8]. Of particular interest is our recent identification of IFN-β as a novel antiinflammatory therapeutic target that stimulates innate production of IL-10 through activation of the GSK3 INHIBITION PREVENTS PERIODONTITIS
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