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Ursodeoxycholic acid attenuates the expression of proinflammatory cytokines in periodontal cells.

ABSTRACT: BACKGROUND:Ursodeoxycholic acid (UDCA) is one of the first-line therapeutic medications used in treatment of cholestatic liver disease. Considering that periodontitis is epidemiologically linked to liver diseases, the question arises weather UDCA holds anti-inflammatory properties on periodontal health. Herein, we provide information that support anti-inflammatory effects of UDCA on three different periodontium-related cell types. METHODS:Gingival fibroblasts and the oral human squamous carcinoma cell line HSC-2 were exposed to interleukin (IL)1? and tumor necrosis factor (TNF)? with and without UDCA. Murine RAW 264.7 macrophages were incubated with sterile-filtered human saliva also in the presence of UDCA. The expression of inflammatory cytokines was measured by reverse transcription-polymerase chain reaction. Immunoassay was applied to detect the production of IL6. Immunostaining was performed for the p65 subunit to further support the anti-inflammatory role of UDCA. RESULTS:We report here that UDCA significantly reduced the IL1? and TNF?-induced expression of IL1, IL6, and IL8 in gingival fibroblasts and the HSC-2 cell line. In RAW 264.7 macrophages, UDCA attenuated the expression of IL1?, IL1?, and IL6 that was increased by saliva. Immunoassay confirmed the capacity of UDCA to reduce inflammation-induced production of IL6 in gingival fibroblasts, HSC-2 and RAW 264.7 cells. Immunostaining revealed the blocking of nuclear translocation of p65 in gingival fibroblasts. CONCLUSIONS:Taken together, UDCA can attenuate the provoked expression of inflammatory cytokines in oral fibroblasts, oral human squamous carcinoma cells and macrophages in vitro. These data support the hypothesis that patients with cholestatic liver disease might benefit from UDCA with respect to periodontal health.

SUBMITTER: Talebian R

PROVIDER: S-EPMC7496100 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Ursodeoxycholic acid attenuates the expression of proinflammatory cytokines in periodontal cells.

Talebian Reza R Panahipour Layla L Gruber Reinhard R

Journal of periodontology 20200206 8

<h4>Background</h4>Ursodeoxycholic acid (UDCA) is one of the first-line therapeutic medications used in treatment of cholestatic liver disease. Considering that periodontitis is epidemiologically linked to liver diseases, the question arises weather UDCA holds anti-inflammatory properties on periodontal health. Herein, we provide information that support anti-inflammatory effects of UDCA on three different periodontium-related cell types.<h4>Methods</h4>Gingival fibroblasts and the oral human sq ...[more]

PMID: 31960968

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Project description:UNLABELLED:Cholestasis leads to liver cell death, fibrosis, cirrhosis, and eventually liver failure. Despite limited benefits, ursodeoxycholic acid (UDCA) is the only Food and Drug Administration-approved treatment for cholestatic disorders. Retinoic acid (RA) is a ligand for nuclear receptors that modulate bile salt homeostasis. RA also possesses immunomodulatory effects and is used to treat acute promyelocytic leukemia and inflammatory disorders such as psoriasis, acne, and rheumatoid arthritis. To test whether the supplementation of RA with UDCA is superior to UDCA alone for treating cholestasis, male Sprague-Dawley rats underwent common bile duct ligation (BDL) for 14 days and were treated with phosphate-buffered saline (PBS), UDCA, all-trans retinoic acid (atRA), or UDCA and atRA by gavage. Treatment with UDCA and atRA substantially improved animal growth rates, significantly reduced liver fibrosis and bile duct proliferation, and nearly eliminated liver necrosis after BDL. Reductions in the bile salt pool size and liver hydroxyproline content were also seen with treatment with atRA or atRA and UDCA versus PBS and UDCA. Furthermore, atRA and UDCA significantly reduced liver messenger RNA and/or protein expression of transforming growth factor ?1 (Tgf-?1), collagen 1a1 (Col1A1), matrix metalloproteinase 2 (Mmp2), cytokeratin 19, ?-smooth muscle actin (?-SMA), cytochrome P450 7A1 (Cyp7a1), tumor necrosis factor ?, and interleukin-?1. The molecular mechanisms of this treatment were also assessed in human hepatocytes, hepatic stellate cells, and LX-2 cells. atRA alone or in combination with UDCA greatly repressed CYP7A1 expression in human hepatocytes and significantly inhibited COL1A1, MMP2, and ?-SMA expression and/or activity in primary human hepatic stellate cells and LX-2 cells. Furthermore, atRA reduced TGF-?1-induced Smad2 phosphorylation in LX-2 cells. CONCLUSION:Our findings indicate that the addition of RA to UDCA reduces the bile salt pool size and liver fibrosis and might be an effective supplemental therapy with UDCA for cholestatic diseases.

Project description:In the lacrimal gland, myoepithelial cells (MEC) express muscle contractile proteins such as alpha smooth muscle actin (SMA) and calponin and therefore can contract to help expel lacrimal fluid. In a previous study, we demonstrated that lacrimal gland MEC express the oxytocin receptor (OXTR) and they contract under oxytocin (OXT) stimulation. Using NOD and MRL/lpr mice (animal models of Sjogren's syndrome), we reported a decrease in SMA and calponin protein levels plus a decline in acini contraction after stimulation with OXT. It is known that proinflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α) or interferon gamma (IFN-γ), can affect OXTR expression and signaling capacity and inhibit MEC contraction. The aim of the current study was to investigate if proinflammatory cytokines are implicated in the loss of MEC contractile ability. Thus, lacrimal gland MEC from a SMA-GFP transgenic mouse were treated with IL-1β (10 ng/ml) for a total of 7 days. At days 0, 2, 4 and 7, GFP intensity, cell size/area, contractile proteins amounts and MEC contraction were assessed. At day 0, control and treated cells showed no differences in GFP intensity and cell size. GFP intensity started to decrease in treated MEC at day 2 (20%; p=0.02), continuing after day 4 (25%; p=0.007) and 7 (30%; p=0.0001). Mean cell area was also reduced at day 2 (34%; p=0.0005), and after 4 (51%; p<0.0001) and 7 days (30%; p=0.0015). The contraction assay at day 2 showed a 70% decrease of contraction in treated MEC (p<0.0001), 73% (p<0.0001) at day 4 and 82% (p=0.0015) at day 7 when compared to control. Levels of contractile proteins were measured on day 7 showing a decrease in SMA and calponin amount in treated MEC compared with the control group (around 30%; p=0.0016 and p=0.0206; respectively). Similar results were observed when TNF-α and IFN-γ were added along with IL-1β. Taken together the present data and those from our previous studies with Sjogren's syndrome mouse models, they strongly suggest that proinflammatory cytokines affect lacrimal gland MEC contractile ability that may account for the reduced tear secretion associated with Sjogren's syndrome dry eye disease.

Project description:PURPOSE:Proinflammatory cytokines interferon gamma (IFN-?), tumor necrosis factor alpha (TNF-?), and interleukin-1 beta (IL-1?) secreted by infiltrating lymphocytes or macrophages may play a role in triggering RPE dysfunction associated with age-related macular degeneration (AMD). Binding of these proinflammatory cytokines to their specific receptors residing on the RPE cell surface can activate signaling pathways that, in turn, may dysregulate cellular gene expression. The purpose of the present study was to investigate whether IFN-?, TNF-?, and IL-1? have an adverse effect on the expression of genes essential for RPE function, employing the RPE cell line ARPE-19 as a model system. METHODS:ARPE-19 cells were cultured for 3-4 months until they exhibited epithelial morphology and expressed mRNAs for visual cycle genes. The differentiated cells were treated with IFN-?, TNF-?, and/or IL-1?, and gene expression was analyzed with real-time PCR analysis. Western immunoblotting was employed for the detection of proteins. RESULTS:Proinflammatory cytokines (IFN-? + TNF-? + IL-1?) greatly increased the expression of chemokines and cytokines in cultured ARPE-19 cells that exhibited RPE characteristics. However, this response was accompanied by markedly decreased expression of genes important for RPE function, such as CDH1, RPE65, RDH5, RDH10, TYR, and MERTK. This was associated with decreased expression of the genes MITF, TRPM1, and TRPM3, as well as microRNAs miR-204 and miR-211, which are known to regulate RPE-specific gene expression. The decreased expression of the epithelial marker gene CDH1 was associated with increased expression of mesenchymal marker genes (CDH2, VIM, and CCND1) and epithelial-mesenchymal transition (EMT) promoting transcription factor genes (ZEB1 and SNAI1). CONCLUSIONS:RPE cells exposed to proinflammatory cytokines IFN-?, TNF-?, and IL-1? showed decreased expression of key genes involved in the visual cycle, epithelial morphology, and phagocytosis. This adverse effect of proinflammatory cytokines, which could be secreted by infiltrating lymphocytes or macrophages, on the expression of genes indispensable for RPE function may contribute to the RPE dysfunction implicated in AMD pathology.

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Ursodeoxycholic acid attenuates the expression of proinflammatory cytokines in periodontal cells.

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Ursodeoxycholic acid attenuates the expression of proinflammatory cytokines in periodontal cells.

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