miR-146a regulates inflammatory cytokine production in Porphyromonas gingivalis lipopolysaccharide-stimulated B cells by targeting IRAK1 but not TRAF6

Jiang, Shiwei; Hu, Yang; Deng, Shu; Deng, Jiayin; Yu, Xinbo; Huang, Grace; Kawai, Toshihisa; Han, Xiaozhe

doi:10.1016/j.bbadis.2017.12.035

Cited by 33 publications

(32 citation statements)

References 29 publications

(57 reference statements)

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“…In this context, miRNAs regulating post‐transcriptional gene expression through the mRNA silencing could play an important role. In fact, miRNA‐146a decreased the mRNA expression levels of IL‐1β and IL‐6 in Porphyromonas gingivalis ‐stimulated B cells, and these suppressor effects were reversed in the presence of a specific miRNA‐146a inhibitor (Jiang et al, ). In macrophages, 12 upregulated miRNAs and 22 downregulated miRNAs have been described after stimulation with A. actinomycetemcomitans (Naqvi, Fordham, Khan, & Nares, ).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of serotype a of Aggregatibacter actinomycetemcomitans on the increased destructive potential of serotype b

et al. 2019

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Objective The serotype b of Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) induces higher cytokine production in dendritic cells (DCs) compared with the other serotypes. However, this increased immunostimulatory potential was modified when DCs were co‐infected with the other A. actinomycetemcomitans serotypes. This study aimed to analyze whether the production of interferon gamma (IFN‐γ), C‐reactive protein (CRP), matrix metalloproteinase (MMP)‐2, and MMP‐9, as well as the activity of osteoclasts, also varies when DCs are co‐infected with the A. actinomycetemcomitans serotypes. Materials and Methods Human DCs were stimulated with the A. actinomycetemcomitans serotypes using the following stimulatory conditions: serotype a/b/c/a+b/a+c/b+c/a+b+c. The IFN‐γ, CRP, and MMP‐2 levels were quantified by ELISA. The active form of MMP‐9 was quantified using fluorescent functional assays. The MMP‐2 gelatinolytic activity was identified by zymogram. The osteoclast activity was determined by quantifying the TRAP expression and resorption‐pit formation using cytochemistry and osteoassays. Results Higher levels of IFN‐γ, CRP, MMP‐2, MMP‐9, and osteoclast activity were detected when DCs were stimulated with the serotype b of A. actinomycetemcomitans compared with the others. This increased immunostimulatory potential attributed to serotype b diminished when DCs were co‐infected with the serotype a. Conclusions This study provides new insights into the virulence of A. actinomycetemcomitans and reveals important differences in the immunostimulatory and pro‐destructive potential among its serotypes.

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Section: Discussionmentioning

confidence: 99%

Inhibitory effect of serotype a of Aggregatibacter actinomycetemcomitans on the increased destructive potential of serotype b

et al. 2019

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“…Our recent study showed that miR-146a inhibited inflammatory cytokine secretion in B cells after challenged with P. gingivalis LPS and decreased bone resorption in experimental periodontits animal models [24]. Moreover, it was found that miR-146a negatively regulated TLR2-induced inflammatory response in keratinocytes [43] and expression of TLR2 was repressed by miR-146a in HEK293T cells [44].…”

Section: Discussionmentioning

confidence: 99%

“…The ligation day was recorded as day 0, and the ligature remained in place for 2 weeks. For group 3 and group 4, each mouse received palatal gingival injections of 2 μL of anti-RANKL antibody (500 μg/mL, Peprotech, Rocky Hill, NJ) or miR-146a (100 nM, GeneCopoeia, Rockville, MD) on the mesial and distal gingival papillae of implant by a 31-gauge double-beveled MicroFine needle (Becton, Dickinson) as these doses were established from our previous publications [24,28]. The injections for animals were administered three times on days 3, 6, and 9, and all the mice were euthanized by CO 2 inhalation on day 14.…”

Section: Micementioning

confidence: 99%

“…Recent studies showed that miRs are important regulators in periodontitis [21][22][23]. Our previous studies demonstrated that miR-146a regulated the cytokine secretion in human gingival fibroblasts and periodontal ligament cells and inhibits inflammatory cytokine production in B cells through directly targeting IRAK1, suggesting a regulatory role of miR-146a in immune-mediated periodontal inflammation [24]. However, the role of miR-146a in peri-implantitis remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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RANKL blockade alleviates peri-implant bone loss and is enhanced by anti-inflammatory microRNA-146a through TLR2/4 signaling

Pan

Hu²,

Wang³

et al. 2020

Int J Implant Dent

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Background: The present study was to determine the effect of local anti-RANKL antibody administration in the presence or absence of microRNA-146a on ligature-induced peri-implant bone resorption, and the potential role of TLR2/4 signaling in such effect.Results: Titanium implants were placed in the left maxilla alveolar bone 6 weeks after extraction of first and second molars in C57/BL6 wild-type (WT) and TLR2 −/− TLR4 −/− (TLR2/4 KO) mice. Silk ligatures were tied around the implants 4 weeks after implantation. Anti-RANKL antibody (500 μg/mL) with or without microRNA 146a (miR-146a) (100 nM) was injected into palatal gingiva around implant on days 3, 6, and 9 during 2 weeks of ligation period. Bone resorption around the implants was assessed by 2D imaging using area measurement and 3D imaging using micro-computed tomography (μCT). Real-time quantitative PCR (RT-qPCR) was used to determine the peri-implant gingival mRNA expression levels of pro-inflammatory cytokines (TNF-α) and osteoclastogenesis-related cytokines (RANKL). In both WT and TLR2/4 KO mice, the bone resorption around implants was significantly increased in the ligation only group when compared to the non-ligation group, but TLR2/4 KO mice showed significantly less bone loss compared to WT mice after ligation. As expected, gingival injection of anti-RANKL antibody significantly reduced bone loss compared with the ligation only group in both WT and TLR2/4 KO mice. Moreover, injection of miR-146a in addition to anti-RANKL antibody significantly enhanced the inhibition of bone loss in WT mice but not in TLR2/4 KO mice. Gingival mRNA expressions of RANKL were significantly reduced by anti-RANKL antibody treatment in both WT and TLR2/4 KO mice but were not affected by the additional miR-146a treatment. Gingival mRNA expression of TNF-α was significantly reduced by miR-146a treatment in WT mice but not in TLR2/4 KO mice. The number of gingival inflammatory cell infiltration and peri-implant TRAP-positive cell formation was significantly reduced by the additional miR-146a treatment in WT mice but not in TLR2/4 KO mice.Conclusions: This study suggests that anti-inflammatory miR-146a enhance anti-RANKL-induced inhibition of periimplant bone resorption through the regulation of TLR2/4 signaling and inhibition of TNF-α expression.

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“…15,16 In addition, previous studies showed that miR-146a regulated the proinflammatory cytokine expression in human fibroblasts and HPDLFs, and it may be a negative regulator in inflammation response after stimulated with P. gingivalis LPS though IRAK1 and NF-B. 17,18 However, other studies showed that miR-146a not targeted IRAK1 or TRAF6 in epithelial and B cells, 19,20 and it did not strongly suppress the production of proinflammatory cytokines in THP-1 monocytes stimulated by P. gingivalis LPS. 21 Furthermore, p38 MAPK is involved in the inflammatory signaling pathways activated by P. gingivalis LPS.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐146a negatively regulates the inflammatory response to Porphyromonas gingivalis in human periodontal ligament fibroblasts via TRAF6/p38 pathway

Tang

Bai

et al. 2018

Journal of Periodontology

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Background Human periodontal ligament fibroblasts (HPDLFs) represent the first line of defense against pathogens in the periodontal tissue. Porphyromonas gingivialis (P. gingivalis) has been known to be most strongly associated with periodontitis. MicroRNA (miR)‐146a is involved in the inflammatory regulation of periodontitis. However, the regulatory mechanism of miR‐146a on in P. gingivalis‐induced inflammation response in HPDLFs was still unclear. The aim of this study was to investigate whether miR‐146a plays a key role in P. gingvalis‐induced inflammation responses through regulation of TRAF6 in HPDLFs. Methods MiR‐146a expression was measured by real‐time polymerase chain reaction (PCR) in HPDLFs stimulated with P. gingivalis and its lipopolysaccharide (LPS). IL‐1ß, IL‐6, and IL‐8 were determined by enzyme‐linked immunosorbent assay (ELISA) in the culture supernatants of HPDLFs after transfected with miR‐146a mimic or inhibitor. Meanwhile, the expression of TRAF6 was measured by real‐time PCR and Western blot. Then, we used luciferase reporter assay to detect whether miR‐146a binds to the 3′‐UTR of TRAF6. By using small interfering RNA (siRNA) of TRAF6, the phosphorylation of p38 mitogen‐activated protein kinase (MAPK) was measured by Western blot. Finally, after inhibition of TRAF6 and p38 in HPDLFs, we analyzed the expression of miR‐146a upon P. gingivalis challenge. Results P. gingivalis and its LPS significantly induced miR‐146a expression in HPDLFs. Overexpression of miR‐146a significantly suppressed the IL‐1ß, IL‐6 and IL‐8 secretion, TRAF6 expression, and p38 phosphorylation. In contrast, the levels of these indexes significantly increased by inhibition of miR‐146a. Furthermore, MiR‐146a directly binds to the 3′‐UTR of TRAF6 in P. gingivalis‐induced HPDLFs, but not in P. gingivalis LPS stimulation. Suppression of TRAF6 could inhibit the phosphorylation of p38. Finally, inhibition of TRAF6 and p38 significantly abolished P. gingivalis‐induced miR‐146a upregulation in HPDLFs. Conclusions MiR‐146a contribute to negative regulation of P. gingivalis‐induced proinflammatory cytokines secretion in HPDLFs though TRAF6/p38 MAPK pathway. Maintaining miR‐146a homeostasis plays a key role in controlling inflammatory response in periodontal tissues.

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miR-146a regulates inflammatory cytokine production in Porphyromonas gingivalis lipopolysaccharide-stimulated B cells by targeting IRAK1 but not TRAF6

Cited by 33 publications

References 29 publications

Inhibitory effect of serotype a of Aggregatibacter actinomycetemcomitans on the increased destructive potential of serotype b

Inhibitory effect of serotype a of Aggregatibacter actinomycetemcomitans on the increased destructive potential of serotype b

RANKL blockade alleviates peri-implant bone loss and is enhanced by anti-inflammatory microRNA-146a through TLR2/4 signaling

MicroRNA‐146a negatively regulates the inflammatory response to Porphyromonas gingivalis in human periodontal ligament fibroblasts via TRAF6/p38 pathway

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