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TAS2R16 Activation Suppresses LPS-Induced Cytokine Expression in Human Gingival Fibroblasts.

ABSTRACT: Sustained and non-resolved inflammation is a characteristic of periodontitis. Upon acute inflammation, gingival fibroblasts release cytokines to recruit immune cells to counter environmental stimuli. The intricate regulation of pro-inflammatory signaling pathways, such as NF-κB, is necessary to maintain periodontal homeostasis. Nonetheless, how inflammation is resolved has not yet been elucidated. In this study, 22 subtypes of taste receptor family 2 (TAS2Rs), as well as the downstream machineries of Gα-gustducin and phospholipase C-β2 (PLCβ2), were identified in human gingival fibroblasts (HGFs). Various bitter agonists could induce an intensive cytosolic Ca²⁺ response in HGFs. More importantly, TAS2R16 was expressed at a relatively high level, and its agonist, salicin, showed robust Ca²⁺ evocative effects in HGFs. Activation of TAS2R16 signaling by salicin inhibited the release of lipopolysaccharide (LPS)-induced pro-inflammatory cytokines, at least in part, by repressing LPS-induced intracellular cAMP elevation and NF-κB p65 nuclear translocation in HGFs. These findings indicate that TAS2Rs activation in HGFs may mediate endogenous pro-inflammation resolution by antagonizing NF-κB signaling, providing a novel paradigm and treatment target for the better management of periodontitis.

SUBMITTER: Zhou Z

PROVIDER: S-EPMC8714777 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Expression profile of human gingival fibroblasts induced by interleukin-1beta reveals central role of nuclear factor-kappa B in stabilizing human gingival fibroblasts during inflammation.

Project description:BackgroundInterleukin (IL)-1beta is a key cytokine in the pathogenesis of periodontitis, and it induces inflammatory mediators in periodontal diseases. We developed immortalized human gingival fibroblasts (HGFs), investigated the effects of IL-1beta on the gene expression using expression arrays containing approximately 40,000 genes, and tested the role of nuclear factor-kappa B (NF-kappaB) in maintaining an activated HGF population.MethodsTotal RNA was isolated from IL-1beta-induced and mock-induced control cells. Gene expression analyses were performed using expression arrays and confirmed by quantitative real-time polymerase chain reaction. Western blot analysis to show inhibitor of kappa B-alpha (IkappaBalpha) phosphorylation and immunostaining of cells for NF-kappaB nuclear translocation were performed. Apoptosis was confirmed by assay of poly ADP-ribose polymerase (PARP) cleavage.ResultsA total of 382 probe sets corresponding to 254 genes were differentially expressed in IL-1beta-induced cells (P <0.001). A total of 215 genes were upregulated, and 39 genes were downregulated. Most notable NF-kappaB pathway members (NFkappaB1, NFkappaB2, IkappaBalpha, IkappaBepsilon, IkappaBzeta, REL, RELB, and TA-NFKBH) were upregulated. IkappaBalpha was phosphorylated, and NF-kappaB accumulated in the nucleus. An IL-1beta-induced set of 27 genes was downregulated by an NF-kappaB inhibitor, leading to a decreased number of viable cells and suggesting an antiapoptotic role for NF-kappaB.ConclusionsIL-1beta leads to a large number of significant expression changes consistent with a pathologic role in periodontitis, including enhancement of inflammatory cytokines, chemokines, transcription factors, matrix metalloproteinases, adhesion molecules, and especially NF-kappaB-dependent antiapoptotic genes. NF-kappaB activation blocks apoptosis, thereby stabilizing the HGF population in inflammation.

| S-EPMC4150685 | biostudies-literature

MAT2A inhibition suppresses inflammation in <i>Porphyromonas gingivalis</i>-infected human gingival fibroblasts.

Project description:BackgroundMethionine adenosyl transferase II alpha (MAT2A) is the key enzyme to transform methionine into S-adenosylmethionine (SAM), the main methylgroup donor involved in the methylation. The purpose of our study wasto explore whether MAT2A-mediated methionine metabolism affected theexpression of inflammatory cytokines in human gingival fibroblasts(hGFs).MethodsBoth healthy and inflamed human gingiva were collected. HGFs werecultured and treated with P. gingivalis, with or without MAT2Ainhibitor (PF9366), small interference RNA (siRNA), or extrinsic SAMpretreatment. The levels of inflammatory cytokines were detected byreal-time PCR, western blotting, and ELISA. SAM levels were detectedby ELISA. The nuclear factor-kappa B (NF-κB) and mitogen-activatedprotein kinase (MAPK) pathway was explored by western blotting.ResultsThe expression of MAT2A was increased in the inflamed tissues. P.gingivalis infection promoted the expression of MAT2A and SAM inhGFs. Meanwhile, PF9366 and MAT2A-knockdown significantly decreasedexpression of inflammatory cytokines and SAM production. PF9366inhibited activation of NF-κB/MAPK pathway in P. gingivalis-treatedhGFs.ConclusionsMAT2A-mediated methionine metabolism promoted P. gingivalis-inducedinflammation in hGFs. Targeting MAT2A may provide a novel therapeuticmethod for modulating periodontitis.

| S-EPMC10732205 | biostudies-literature

Expression of deubiquitinases in human gingiva and cultured human gingival fibroblasts.

Project description:BackgroundAlthough deubiquitinating enzymes (DUBs) such as CYLD, A20 and OTULIN are expressed in multiple tissues and thought to be linked with inflammatory diseases, their expression in periodontal tissues remains to be determined. This research was designed to assess the expression of CYLD, A20 and OTULIN in human gingiva, and to evaluate the regulation of these DUBs in human gingival fibroblasts (HGFs) upon different stimuli.MethodsImmunohistochemistry assay was conducted to determine the expression of CYLD, A20 and OTULIN in human gingiva. Immunofluorescence assay was employed to observe the protein expression of CYLD, A20 and OTULIN in HGFs. RT-PCR and western blots were carried out to assess gene and protein expression changes of these DUBs in HGFs upon LPS or TNF-α.ResultsCYLD, A20 and OTULIN were found to be expressed in human gingiva and HGFs. The expression of CYLD, A20 and OTULIN was lower in the inflamed gingival tissue samples compared with the healthy gingival tissue samples. Further, the expression of CYLD, A20 and OTULIN in HGFs exhibited distinct regulation by different stimuli. TNF-α treatment markedly increased NF-κB activation in HGFs CONCLUSIONS: Our findings suggest that CYLD, A20 and OTULIN might play a role in the progression of periodontitis.

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Fungal metabolite (+)-terrein suppresses IL-6/sIL-6R-induced CSF1 secretion by inhibiting JAK1 phosphorylation in human gingival fibroblasts.

Project description:Control of bacterial infection-induced inflammatory responses is one of the effective therapeutic approaches of periodontal diseases. Natural products such as lipid mediators and metabolites from microorganisms have been used for decreasing inflammation. We previously reported that (+)-terrein inhibited activation of STAT3 and ERK1/2 in interleukin-6 (IL-6) signaling cascade, leading to prevent vascular endothelial growth factor (VEGF) secretion in human gingival fibroblasts (HGFs). However, little is still known about the role of (+)-terrein on inflammatory responses. In this study, we provided the possibility of novel action that (+)-terrein inhibits activation of Janus-activated kinase 1 (JAK1), which has a central function in IL-6 signaling cascade, and alters expression of mRNAs and proteins induced by IL-6/soluble IL-6 receptor (sIL-6R) stimulation in HGFs. First, we performed PCR array to examine IL-6/sIL-6R-induced mRNA expression, and then expression of mRNA and protein of colony stimulating factor-1 (CSF1) and VEGF were clearly determined by quantitative RT-PCR and ELISA, respectively. Treatment with (+)-terrein suppressed expression of mRNA and protein of CSF1 and VEGF by IL-6/sIL-6R stimulation. Next, to test the effect of (+)-terrein on IL-6/sIL-6R signaling cascade, we demonstrated whether (+)-terrein affects phosphorylation of JAK1 and its downstream proteins, Akt and SHP-2. Western blotting revealed that (+)-terrein inhibited IL-6/sIL-6R-induced phosphorylation of JAK1, Akt, and SHP-2. Therefore, (+)-terrein suppresses IL-6/sIL-6R-induced expression of CSF1 and VEGF via inhibition of JAK1, Akt, and SHP-2. Based on our results, we suggest that (+)-terrein is a candidate compound for anti-inflammatory effect associated with IL-6 signaling.

| S-EPMC6260243 | biostudies-literature

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| S-EPMC7400382 | biostudies-literature

Heterogeneous Porphyromonas gingivalis LPS modulates immuno-inflammatory response, antioxidant defense and cytoskeletal dynamics in human gingival fibroblasts.

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Necroptosis suppresses inflammation via termination of TNF- or LPS-induced cytokine and chemokine production.

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| S-EPMC4495357 | biostudies-literature

Juglone Suppresses LPS-induced Inflammatory Responses and NLRP3 Activation in Macrophages.

Project description:The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome has been implicated in a variety of diseases, including atherosclerosis, neurodegenerative diseases, and infectious diseases. Thus, inhibitors of NLRP3 inflammasome have emerged as promising approaches to treat inflammation-related diseases. The aim of this study was to explore the effects of juglone (5-hydroxyl-1,4-naphthoquinone) on NLRP3 inflammasome activation. The inhibitory effects of juglone on nitric oxide (NO) production were assessed in lipopolysaccharide (LPS)-stimulated J774.1 cells by Griess assay, while its effects on reactive oxygen species (ROS) and NLRP3 ATPase activity were assessed. The expression levels of NLRP3, caspase-1, and pro-inflammatory cytokines (IL-1β, IL-18) and cytotoxicity of juglone in J774.1 cells were also determined. Juglone was non-toxic in J774.1 cells when used at 10 μM (p < 0.01). Juglone treatment inhibited the production of ROS and NO. The levels of NLRP3 and cleaved caspase-1, as well as the secretion of IL-1β and IL-18, were decreased by treatment with juglone in a concentration-dependent manner. Juglone also inhibited the ATPase activities of NLRP3 in LPS/ATP-stimulated J774.1 macrophages. Our results suggested that juglone could inhibit inflammatory cytokine production and NLRP3 inflammasome activation in macrophages, and should be considered as a therapeutic strategy for inflammation-related diseases.

| S-EPMC7412499 | biostudies-literature

Carbon Monoxide-Releasing Molecule-3 Suppresses Tumor Necrosis Factor-?- and Interleukin-1?-Induced Expression of Junctional Molecules on Human Gingival Fibroblasts via the Heme Oxygenase-1 Pathway.

Project description:Human gingival fibroblast barrier dysfunction caused by inflammation contributes to gingivitis and can lead to inflammatory periodontal disease. The disease features include upregulated epithelial permeability, increased inflammatory mediators, and downregulated junctional complex molecules. Carbon monoxide- (CO-) releasing molecule-3 (CORM-3) is a water-soluble compound that has demonstrated anti-inflammatory effects in in vitro and in vivo studies. In this study, we aimed to investigate the effects of CORM-3 on the expression of tight and adherens junction molecules on human gingival fibroblasts (HGFs) stimulated with tumor necrosis factor-? (TNF-?) and interleukin-1? (IL-1?). HGFs were cultured from the explants of normal human gingival tissues, which were stimulated in the presence or absence of CORM-3. Epithelial barrier function was evaluated by paracellular permeability and junctional complex molecule expression analyses. The protein and mRNA expression levels of adherens junction molecules (VE-cadherin and ?-catenin) and tight junction molecules (zona occludens-1, ZO-1) were studied using western blot analysis and reverse transcription-quantitative polymerase chain reaction (RT-PCR). The mRNA and protein expression levels of these cytokines were also analyzed in HGFs transiently transfected with HO-1 small interfering RNA (siRNA) in response to TNF-? and IL-1? stimulation. CORM-3 reduced permeability and enhanced the expression of junctional complex molecules (ZO-1, VE-cadherin, and ?-catenin) in TNF-?- and IL-1?-induced HGFs. However, these effects of CORM-3 were attenuated when HO-1 siRNA was transiently transfected in HGFs. These findings indicate that CORM-3 exerts anti-inflammatory effects on TNF-?- and IL-1?-stimulated HGFs via the HO-1 pathway, which suggests the promising potential of CORM-3 in the treatment of inflammatory periodontal disease.

| S-EPMC7204158 | biostudies-literature

Expression of vitamin D 1?-hydroxylase in human gingival fibroblasts in vivo.

Project description:BackgroundVitamin D 1?-hydroxylase CYP27B1 is the key factor in the vitamin D pathway. Previously, we analyzed the expression of CYP27B1 in human gingival fibroblasts in vitro. In the present study, we analyzed the gingival expression of CYP27B1 in vivo.MethodsForty-two patients with periodontitis Stage IV Grade C and 33 controls were recruited. All patients with periodontitis had unsalvageable teeth and part of the wall of the periodontal pocket was resected and obtained after tooth extraction. All controls needed crown-lengthening surgery, and samples of gingiva resected during surgery were also harvested. All the individuals' gingivae were used for immunohistochemistry and immunofluorescence. In addition, gingivae from seventeen subjects of the diseased group and twelve subjects of the control group were analyzed by real-time PCR.ResultsExpression of CYP27B1 was detected both in gingival epithelia and in gingival connective tissues, and the expression in connective tissues colocalized with vimentin, indicating that CYP27B1 protein is expressed in gingival fibroblasts. The expression of CYP27B1 mRNA in gingival connective tissues and the CYP27B1 staining scores in gingival fibroblasts in the diseased group were significantly higher than those in the control group.ConclusionsExpression of CYP27B1 in human gingival tissues was detected, not only in the fibroblasts of gingival connective tissues, but also in the gingival epithelial cells, and might be positively correlated with periodontal inflammation.

| S-EPMC7789863 | biostudies-literature

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