Tormentic acid inhibits LPS-induced inflammatory response in human gingival fibroblasts via inhibition of TLR4-mediated NF-κB and MAPK signalling pathway

The present study was aimed at investigating whether human Periodontal Ligament Stem Cells (hPDLSCs) were capable of sensing and reacting to lipopolysaccharide from Porphyromonas gingivalis (LPS-G) which is widely recognized as a major pathogen in the development and progression of periodontitis. At this purpose hPDLCs were stimulated with 5 μg/mL LPS-G at various times and the expression of toll-like receptor 4 (TLR4) was evaluated. Toll-like receptors (TLRs) play an essential role in innate immune signaling in response to microbial infections, and in particular TLR4, type-I transmembrane proteins, has been shown recognizing LPS-G. Our results put in evidence, in treated samples, an overexpression of TLR4 indicating that, hPDLSCs express a functional TLR4 receptor. In addition, LPS-G challenge induces a significant cell growth decrease starting from 24 h until 72 h of treatment. LPS-G leads the activation of the TLR4/MyD88 complex, triggering the secretion of proinflammatory cytokines cascade as: IL-1α, IL-8, TNF-α and β and EOTAXIN. Moreover, the upregulation of pERK/ERK signaling pathways and NFkB nuclear translocation was evident. On the basis of these observations, we conclude that hPDLSCs could represent an appropriate stem cells niche modeling leading to understand and evaluate the biological mechanisms of periodontal stem cells in response to LPS-G, mimicking in vitro an inflammatory process occurring in vivo in periodontal disease.

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“…17 LPS from Porphyromonas gingivalis has been identified as the master factor inducing periodontal disease.…”

Section: Discussionmentioning

confidence: 99%

MyD88/ERK/NFkB pathways and pro-inflammatory cytokines release in periodontal ligament stem cells stimulated by Porphyromonas gingivalis

et al. 2017

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“…NF-kB, which is a transcription factor, has an important role in immune and inflammatory responses, [35][36][37][38] and its dysregulation has been associated with a number of inflammation- related diseases or disorders, including sepsis and septic shock, 39 cardiovascular disease, asthma, atherosclerosis, diabetes, obesity and cancer. [40][41][42] IL-6, TNF-α, CXCL-1 and iNOS are regulated through the NF-kB pathway.…”

Section: Discussionmentioning

confidence: 99%

BRD7 plays an anti-inflammatory role during early acute inflammation by inhibiting activation of the NF-кB signaling pathway

et al. 2016

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Increasing evidence has shown a strong association between tumor-suppressor genes and inflammation. However, the role of BRD7 as a novel tumor suppressor in inflammation remains unknown. In this study, by observing BRD7 knockout mice for 6-12 months, we discovered that compared with BRD7 mice, BRD7 mice were more prone to inflammation, such as external inflammation and abdominal abscess. By using mouse embryo fibroblast (MEF) cells from the BRD7 knockout mouse, an in vitro lipopolysaccharide (LPS)-stimulated MEF cell line was established. The mRNA levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), chemokine (C-X-C motif) ligand 1 (CXCL-1) and inducible nitric oxide synthase (iNOS) were significantly increased in BRD7 MEF cells compared with BRD7 MEF cells after LPS stimulation for 1 or 6 h. In addition, the cytoplasm-to-nucleus translocation of nuclear factor kappa-B (NF-κB; p65) and an increased NF-κB reporter activity were observed in BRD7 MEF cells at the 1 h time point but not at the 6 h time point. Furthermore, an in vivo dextran sodium sulfate (DSS)-induced acute colitis model was created. As expected, the disease activity index (DAI) value was significantly increased in the BRD7 mice after DSS treatment for 1-5 days, which was demonstrated by the presence of a significantly shorter colon, splenomegaly and tissue damage. Moreover, higher expression levels of IL-6, TNF-α, p65, CXCL-1 and iNOS, and an increased level of NF-κB (p65) nuclear translocation were also found in the DSS-treated BRD7 mice. These findings suggest that BRD7 has an anti-inflammatory role during early acute inflammation by inhibiting activation of the NF-кB signaling pathway, which provides evidence to aid in understanding the therapeutic effects of BRD7 on inflammatory diseases.

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“…Therefore, TLRs mediate NF-κB activation, participate in the inflammatory response, and cause changes in the IL-6 and IL-8 levels [16][17][18]. TLR4/MyD88/p65 is upregulated and the number of inflammatory cells is relatively high in the intestinal mucosae of patients with ulcerative colitis.…”

Section: Introductionmentioning

confidence: 99%

Heat stress induced gut microbiota changes activate TLR4 / NF-κB signaling pathway contributing to inflammatory bowel disease in pigs

Hu¹,

Patil²,

Gong³

et al. 2020

Preprint

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Background Various stressors alter the 'brain-gut axis' and contribute to many gastrointestinal disorders such as inflammatory bowel disease. However, the pathological mechanisms of these perturbations are poorly understood. Here, we report on the induction of intestinal inflammation in heat-stressed pigs and apply fecal microbiota transplantation from pigs to mice to elucidate the role of intestinal microbiota in TLR4/NF-κB signaling pathway activation. Results Twelve healthy adult pigs were subjected to heat stress (34 ± 1 °C and 75–85% relative humidity) and compared with 12 control pigs exposed to 25 ± 3 °C and the same humidity level. The pigs were sacrificed on days 1, 7, 14, and 21. Their colonic contents were collected for microbiome analyses and their colonic epithelia underwent transcriptome analyses. Pseudo-germ-free mice were gavaged with fecal bacteria from heat-stressed and control pigs on the collection days to determine whether gut microbiomes and immune responses resembling those in the pigs could be induced in the mice. Heat-stressed pigs presented with fever and diarrhea from day 7 and their colonic villus length, crypt depth/width, and goblet cell number were significantly lower than those of the controls. Their TLR4, TRAF6, and nuclear p65 were upregulated at the RNA and protein levels. Their proinflammatory IL-6, IL-8, and IL-17 were also upregulated. Colonic microflora composition in the heat-stressed pigs markedly differed from that of the controls. By day 14, the former presented with substantial increases in opportunistic pathogens such as Campylobacterales , Veillonellaceae , and Megasphaera . Intestinal lipopolysaccharide concentrations were higher in the heat-stressed than the control pigs. Mice administered fecal transplantation from heat-stressed pigs had a distinctly different colonic microflora composition from those receiving control pig fecal transplantation. Bacteroides were significantly diminished and Akkermansia were significantly augmented in mice administered feces from heat-stressed pigs for 14 d. In the colonic tissues of mice given feces from heat-stressed pigs, the TLR4/NF-κB signaling pathway was activated and there was a mild inflammatory response. Conclusion Heat stress promotes changes in gut microflora composition which, in turn, activates the TLR4/NF-κB signaling pathway and causes inflammatory bowel disease in pigs.

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Tormentic acid inhibits LPS-induced inflammatory response in human gingival fibroblasts via inhibition of TLR4-mediated NF-κB and MAPK signalling pathway

Cited by 45 publications

References 25 publications

MyD88/ERK/NFkB pathways and pro-inflammatory cytokines release in periodontal ligament stem cells stimulated by Porphyromonas gingivalis

MyD88/ERK/NFkB pathways and pro-inflammatory cytokines release in periodontal ligament stem cells stimulated by Porphyromonas gingivalis

BRD7 plays an anti-inflammatory role during early acute inflammation by inhibiting activation of the NF-кB signaling pathway

Heat stress induced gut microbiota changes activate TLR4 / NF-κB signaling pathway contributing to inflammatory bowel disease in pigs

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