Expression of TRAF6 and pro-inflammatory cytokines through activation of TLR2, TLR4, NOD1, and NOD2 in human periodontal ligament fibroblasts

Tang, Lu; Zhou, Xuedong; Wang, Qian; Zhang, Lan; Wang, Yao; Li, Xiaoyü; Huang, Dingming

doi:10.1016/j.archoralbio.2011.02.020

Cited by 77 publications

(73 citation statements)

References 30 publications

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“…Our study concurs with these observations: in response to the invading microbes, NOD2 loss of function in mice stimulates TLR2 signaling by up-regulation of TRAF6 and JNK3, leading to the production of NF-κB and resulting in the overexpression of serum cytokines, which play an important role in alveolar bone resorption in periodontitis and atherosclerosis. The elevated levels of cytokines further substantiate the role of NOD2 in modulating the P. gingivalis effects in this murine periodontitis model and atherosclerosis, especially knowing that NOD2 is expressed in gingival, pulp and periodontal fibroblasts, oral epithelial cells, and vascular endothelial cells (20,(22)(23)(24)(25). Surprisingly, IL-10, an antiinflammatory and antiatherogenic cytokine produced by macrophages, Th1, and B cells, was also significantly elevated in NOD2-deficent mice.…”

Section: Discussionmentioning

confidence: 79%

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Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

Yuan¹,

Zelkha²,

Burkatovskaya³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance Apolipoprotein E −/− (ApoE −/− ) mice deficient in nucleotide binding oligomerization domain-containing protein 2 (NOD2) and subjected to an oral gavage of Porphyromonas gingivalis developed elevated serum inflammatory cytokines, cholesterol, alveolar bone loss, and atherosclerosis. Stimulation of NOD2 by Muramyl DiPeptide (MDP) in ApoE −/− mice reduced P. gingivalis -induced inflammatory cytokines, cholesterol, alveolar bone loss, and atherosclerosis by reducing the expression of inhibitor of NF-κB kinase-β, NF-κB, JNK mRNA, and TNF-α protein levels. A reduction in body weight gain was observed in ApoE −/− mice fed a high-fat diet (HFD) and injected with MDP compared to ApoE −/− mice fed a HFD but saline injected. MDP activation of NOD2 should be considered in the treatment of inflammatory processes affecting atherosclerosis, bone loss, and possibly, weight gain.

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Section: Discussionmentioning

confidence: 79%

“…NOD2 expression and unique functions have also been described in other cell types, including adipocytes, gingival, pulp and periodontal fibroblasts, oral epithelial cells, and vascular endothelial cells (20)(21)(22)(23)(24)(25). However, the precise role of NOD2 in chronic inflammatory diseases remains unclear.…”

Section: Apoementioning

confidence: 99%

Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

Yuan¹,

Zelkha²,

Burkatovskaya³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, the production of osteoclastogenic cytokines, including IL-1β, IL-6, and IL-8, is accelerated by co-stimulation with NOD1 or NOD2 and TLR2 or TLR4 ligands via increased expression of TNF receptor-associated factor 6 (TRAF6) in periodontal NOD2 Mediates Odontoblast Differentiation, RANKL Expression ligament cells (Tang et al, 2011). In addition, MDP synergistically enhances LPS-mediated osteoclast differentiation through increased RANKL expression in osteoblasts (Yang et al, 2005).…”

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confidence: 99%

NOD2 Mediates Odontoblast Differentiation and RANKL Expression

Lee

Kim

et al. 2014

J Dent Res

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The precise regulation of odontoblast differentiation and osteoclastogenic cytokine expression in human dental pulp cells (HDPCs) is crucial for the pathology of bacteria-related pulpitis. Although the up-regulation of nucleotide-binding oligomerization domain-containing protein 2 (NOD2) has been reported in inflamed human dental pulps, the role of NOD2 in the differentiation of HDPCs remains unclear. Here, we show the involvement of NOD2 in odontoblast differentiation together with osteoclastogenic cytokine expression in HDPCs. Treatment with muramyl dipeptide (MDP), a known NOD2-agonist, significantly inhibited odontoblast differentiation of HDPCs, as revealed by reduced ALP activity, osteoblast/ odontoblast marker expression, and mineralized nodule formation. Importantly, the forced down-regulation of NOD2 by small interfering RNA (siRNA) recovered MDP-down-regulated odontoblast differentiation. MDP-elicited suppression of odontoblast differentiation resulted from the increased expression of MKP-1 protein and the subsequent decline of MAPKs phosphorylation, which is a prerequisite for odontoblast differentiation. Furthermore, we found that MDP treatment elevated the expression of osteoclastogenic cytokines in HDPCs, which was also reversed by NOD2 silencing. Analysis of these data, taken together, suggests that the regulation of NOD2 expression upon MDP challenge might serve as an intrinsic mechanism that underlies the hindered dentin formation and accelerated dentin resorption in bacterial infection-mediated pulpitis.Abbreviations: HDPCs, human dental pulp cells; NOD2, nucleotide-binding oligomerization domain-containing protein 2; MDP, muramyl dipeptide; siRNA, small interfering RNA; MAPKs, mitogen-activated protein kinases; MKP-1, MAPK phosphatase-1; BMMs, bone-marrow-derived macrophages; and CM, conditioned medium.

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“…The expression of NOD1 and NOD2 receptors has been evidenced in various cell types of the oral cavity, including periodontal ligament cells (Jeon et al, 2012), pulp fibroblasts (Hirao et al, 2009), gingival fibroblasts (Hosokawa et al, 2010), fibroblasts of periodontal ligament (Tang et al, 2011), and cells of gingival epithelium (Chung et al, 2010). Moreover, it is known that osteoblasts also express NOD1 and NOD2 and are able to recognize and respond to bacterial stimuli by the activation of these receptors (Marriott et al, 2005).…”

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confidence: 99%

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

et al. 2014

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The NOD-like receptors are cytoplasmic proteins that sense microbial by-products released by invasive bacteria. Although NOD1 and NOD2 are functionally expressed in cells from oral tissues and play a role triggering immune responses, the role of NOD2 receptor in the bone resorption and in the modulation of osteoclastogenesis is still unclear. We show that in an experimental model of periodontitis with Porphyromonas gingivalis W83, NOD2-/- mice showed lower bone resorption when compared to wild type. Quantitative polymerase chain reaction analysis revealed that wild-type infected mice showed an elevated RANKL/OPG ratio when compared to NOD2-/- infected mice. Moreover, the expression of 2 osteoclast activity markers—cathepsin K and matrix metalloproteinase 9—was significantly lower in gingival tissue from NOD2-/- infected mice compared to WT infected ones. The in vitro study reported an increase in the expression of the NOD2 receptor 24 hr after stimulation of hematopoietic bone marrow cells with M-CSF and RANKL. We also evaluated the effect of direct activation of NOD2 receptor on osteoclastogenesis, by the activation of this receptor in preosteoclasts culture, with different concentrations of muramyl dipeptide. The results show no difference in the number of TRAP-positive cells. Although it did not alter the osteoclasts differentiation, the activation of NOD2 receptor led to a significant increase of cathepsin K expression. We confirm that this enzyme was active, since the osteoclasts resorption capacity was enhanced by muramyl dipeptide stimulation, evaluated in osteoassay plate. These results show that the lack of NOD2 receptor impairs the bone resorption, suggesting that NOD2 receptor could contribute to the progression of bone resorption in experimental model of periodontitis. The stimulation of NOD2 by its agonist, muramyl dipeptide, did not affect osteoclastogenesis, but it does favor the bone resorption capacity identified by increased osteoclast activity.

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Expression of TRAF6 and pro-inflammatory cytokines through activation of TLR2, TLR4, NOD1, and NOD2 in human periodontal ligament fibroblasts

Cited by 77 publications

References 30 publications

Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

Pivotal role of NOD2 in inflammatory processes affecting atherosclerosis and periodontal bone loss

NOD2 Mediates Odontoblast Differentiation and RANKL Expression

NOD2 Contributes to Porphyromonas gingivalis–induced Bone Resorption

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