scholarly journals 1,25-dihydroxyvitamin D3 suppresses lipopolysaccharide-induced interleukin-6 production through aryl hydrocarbon receptor/nuclear factor-κB signaling in oral epithelial cells

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Hao Li ◽  
Wei Li ◽  
Qi Wang
Keyword(s):  
Epithelial Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Nuclear Factor Κb ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Antiinflammatory Effect ◽  
Oral Epithelial Cells ◽  
Aryl Hydrocarbon ◽  
Oral Epithelial

Abstract Background Antiinflammatory effect of 1,25-dihydroxyvitamin D3 (1,25D3) has been reported in periodontitis, but the exact mechanisms remain unclear. Oral epithelial cells are recently highlighted as an important regulator of inflammation in this disease. This in vitro study was established to investigate the effect of 1,25D3 on key proinflammatory cytokine IL-6 production and aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB) signaling in oral epithelial cells upon the stimulation of lipopolysaccharide (LPS) from periodontal pathogens. Methods OKF6/TERT-2 oral keratinocytes were incubated with LPS and different concentrations of 1,25D3, and levels of IL-6 production were determined using enzyme-linked immunosorbent assay (ELISA). Expression of vitamin D receptor (VDR), and activation of AhR was examined using western blot analysis, and phosphorylation of NF-κB was detected using cell-based protein phosphorylation ELISA. Results 1,25D3 inhibited LPS-induced IL-6 overexpression in OKF6/TERT-2 cells. Additionally, 1,25D3 increased VDR expression and AhR activation, and repressed NF-κB phosphorylation. Furthermore, 1,25D3 suppressed IL-6 expression and enhanced VDR expression and regulated AhR/NF-κB signaling activation in a dose-dependent manner after 48 h treatment. Conclusions These results suggest that 1,25D3 may inhibit LPS-induced IL-6 overexpression in human oral epithelial cells through AhR/NF-κB signaling. Our findings may provide an explanation for the antiinflammatory effect and therapeutic benefit of 1,25D3 in periodontitis.

scholarly journals The Aryl Hydrocarbon Receptor Governs Epithelial Cell Invasion during Oropharyngeal Candidiasis

mBio ◽  
2017 ◽  
Vol 8 (2) ◽  
Author(s):  
Norma V. Solis ◽  
Marc Swidergall ◽  
Vincent M. Bruno ◽  
Sarah L. Gaffen ◽  
Scott G. Filler
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Signaling Pathways ◽  
Oral Epithelium ◽  
New Approach ◽  
Oral Epithelial Cells ◽  
Aryl Hydrocarbon ◽  
Molecule Inhibitor ◽  
Oral Epithelial ◽  
Cell Signaling Pathways

ABSTRACT Oropharyngeal candidiasis (OPC), caused predominantly by Candida albicans, is a prevalent infection in patients with advanced AIDS, defects in Th17 immunity, and head and neck cancer. A characteristic feature of OPC is fungal invasion of the oral epithelial cells. One mechanism by which C. albicans hyphae can invade oral epithelial cells is by expressing the Als3 and Ssa1 invasins that interact with the epidermal growth factor receptor (EGFR) on epithelial cells and stimulate endocytosis of the organism. However, the signaling pathways that function downstream of EGFR and mediate C. albicans endocytosis are poorly defined. Here, we report that C. albicans infection activates the aryl hydrocarbon receptor (AhR), leading to activation of Src family kinases (SFKs), which in turn phosphorylate EGFR and induce endocytosis of the fungus. Furthermore, treatment of oral epithelial cells with interferon gamma inhibits fungal endocytosis by inducing the synthesis of kynurenines, which cause prolonged activation of AhR and SFKs, thereby interfering with C. albicans-induced EGFR signaling. Treatment of both immunosuppressed and immunocompetent mice with an AhR inhibitor decreases phosphorylation of SFKs and EGFR in the oral mucosa, reduces fungal invasion, and lessens the severity of OPC. Thus, our data indicate that AhR plays a central role in governing the pathogenic interactions of C. albicans with oral epithelial cells during OPC and suggest that this receptor is a potential therapeutic target. IMPORTANCE OPC is caused predominantly by the fungus C. albicans, which can invade the oral epithelium by several mechanisms. One of these mechanisms is induced endocytosis, which is stimulated when fungal invasins bind to epithelial cell receptors such as EGFR. Receptor binding causes rearrangement of epithelial cell microfilaments, leading to the formation of pseudopods that engulf the fungus and pull it into the epithelial cell. We discovered AhR acts via SFKs to phosphorylate EGFR and induce the endocytosis of C. albicans. Our finding that a small molecule inhibitor of AhR ameliorates OPC in mice suggests that a strategy of targeting host cell signaling pathways that govern epithelial cell endocytosis of C. albicans holds promise as a new approach to preventing or treating OPC. IMPORTANCE OPC is caused predominantly by the fungus C. albicans, which can invade the oral epithelium by several mechanisms. One of these mechanisms is induced endocytosis, which is stimulated when fungal invasins bind to epithelial cell receptors such as EGFR. Receptor binding causes rearrangement of epithelial cell microfilaments, leading to the formation of pseudopods that engulf the fungus and pull it into the epithelial cell. We discovered AhR acts via SFKs to phosphorylate EGFR and induce the endocytosis of C. albicans. Our finding that a small molecule inhibitor of AhR ameliorates OPC in mice suggests that a strategy of targeting host cell signaling pathways that govern epithelial cell endocytosis of C. albicans holds promise as a new approach to preventing or treating OPC.

scholarly journals Streptococcus gallolyticus Increases Expression and Activity of Aryl Hydrocarbon Receptor-Dependent CYP1 Biotransformation Capacity in Colorectal Epithelial Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Rahwa Taddese ◽  
Rian Roelofs ◽  
Derk Draper ◽  
Xinqun Wu ◽  
Shaoguang Wu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Specific Inhibitor ◽  
Intestinal Bacteria ◽  
Opportunistic Pathogen ◽  
Dependent Manner ◽  
Aryl Hydrocarbon ◽  
Streptococcus Gallolyticus

ObjectiveThe opportunistic pathogen Streptococcus gallolyticus is one of the few intestinal bacteria that has been consistently linked to colorectal cancer (CRC). This study aimed to identify novel S. gallolyticus-induced pathways in colon epithelial cells that could further explain how S. gallolyticus contributes to CRC development.Design and ResultsTranscription profiling of in vitro cultured CRC cells that were exposed to S. gallolyticus revealed the specific induction of oxidoreductase pathways. Most prominently, CYP1A and ALDH1 genes that encode phase I biotransformation enzymes were responsible for the detoxification or bio-activation of toxic compounds. A common feature is that these enzymes are induced through the Aryl hydrocarbon receptor (AhR). Using the specific inhibitor CH223191, we showed that the induction of CYP1A was dependent on the AhR both in vitro using multiple CRC cell lines as in vivo using wild-type C57bl6 mice colonized with S. gallolyticus. Furthermore, we showed that CYP1 could also be induced by other intestinal bacteria and that a yet unidentified diffusible factor from the S. galloltyicus secretome (SGS) induces CYP1A enzyme activity in an AhR-dependent manner. Importantly, priming CRC cells with SGS increased the DNA damaging effect of the polycyclic aromatic hydrocarbon 3-methylcholanthrene.ConclusionThis study shows that gut bacteria have the potential to modulate the expression of biotransformation pathways in colonic epithelial cells in an AhR-dependent manner. This offers a novel theory on the contribution of intestinal bacteria to the etiology of CRC by modifying the capacity of intestinal epithelial or (pre-)cancerous cells to (de)toxify dietary components, which could alter intestinal susceptibility to DNA damaging events.

scholarly journals Glycemia-dependent Nuclear Factor κB Activation Contributes to Mechanical Allodynia in Rats with Chronic Postischemia Pain

2013 ◽  
Vol 119 (3) ◽  
pp. 687-697 ◽  
Author(s):  
Marie-Christine Ross-Huot ◽  
André Laferrière ◽  
Mina Khorashadi ◽  
Terence J. Coderre
Keyword(s):  
Reperfusion Injury ◽  
Dorsal Horn ◽  
Mechanical Allodynia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Nuclear Factor Κb ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Normal Feeding

Abstract Background: Ischemia–reperfusion injury causes chronic postischemia pain (CPIP), and rats with higher glycemia during ischemia–reperfusion injury exhibit increased allodynia. Glycemia-induced elevation of nuclear factor κB (NFκB) may contribute to increased allodynia. Methods: Glycemia during a 3-h ischemia–reperfusion injury was manipulated by: normal feeding; or normal feeding with administration of insulin; dextrose; or insulin/dextrose. In these groups, NFκB was measured in ipsilateral hind paw muscle and spinal dorsal horn by enzyme-linked immunosorbent assay (ELISA), and SN50, an NFκB inhibitor, was administered to determine its differential antiallodynic effects depending on glycemia. Results: CPIP fed/insulin rats (12.03 ± 4.9 g, N = 6) had less allodynia than fed, fed/insulin/dextrose, and fed/dextrose rats (6.29 ± 3.37 g, N = 7; 4.57 ± 3.03 g, N = 6; 2.95 ± 1.10 g, N = 9), respectively. Compared with fed rats (0.209 ± 0.022 AU, N = 7), NFκB in ipsilateral plantar muscles was significantly lower for fed/insulin rats, and significantly higher for fed/dextrose rats (0.152 ± 0.053 AU, N = 6; 0.240 ± 0.057 AU, N = 7, respectively). Furthermore, NFκB in the dorsal horn of fed, fed/insulin/dextrose, and fed/dextrose rats (0.293 ± 0.049 AU; 0.267 ± 0.037 AU; 0.315 ± 0.015 AU, respectively, N = 6 for each) was significantly higher than in fed/insulin animals (0.267 ± 0.037 AU, N = 6). The antiallodynic SN50 dose–response curves of CPIP rats in the fed/insulin/dextrose, fed/dextrose, and fed conditions exhibited a rightward shift compared with the fed/insulin group. The threshold SN50 dose of CPIP fed/dextrose, fed/insulin/dextrose, and fed rats (328.94 ± 92.4 ng, 77.80 ± 44.50 ng, and 24.89 ± 17.20 ng, respectively) was higher than that for fed/insulin rats (4.06 ± 7.04 ng). Conclusions: NFκB was activated in a glycemia-dependent manner in CPIP rats. Hypoglycemic rats were more sensitive to SN50 than rats with higher glycemia. The finding that SN50 reduces mechanical allodynia suggests that NFκB inhibitors might be useful for treating postischemia pain.

scholarly journals Epha2, an epithelial cell pattern recognition receptor for fungal β-glucans

2017 ◽  
Author(s):  
Marc Swidergall ◽  
Norma V. Solis ◽  
Scott G. Filler
Keyword(s):  
Pattern Recognition ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Inflammatory Response ◽  
Pattern Recognition Receptor ◽  
Dependent Manner ◽  
Fungal Burden ◽  
Oral Epithelial Cells ◽  
Oral Epithelial ◽  
Recognition Receptor

Abstract:Oral epithelial cells discriminate between pathogenic and non-pathogenic stimuli, and only induce an inflammatory response when they are exposed to high levels of a potentially harmful microorganism. The pattern recognition receptors (PRRs) in epithelial cells that mediate this differential response are poorly understood. Here, we demonstrate that the ephrin type-A receptor 2 (EphA2) is an oral epithelial cell PRR that binds to exposed β-glucans on the surface of the fungal pathogen Candida albicans. Binding of C. albicans to EphA2 on oral epithelial cells activates signal transducer and activator of transcription 3 (Stat3) and mitogen-activated protein kinase signaling in an inoculum-dependent manner, and is required for induction of a pro-inflammatory and antifungal response. Inhibition of EphA2 in mice decreases IL-17 signaling during oropharyngeal candidiasis, resulting in increased oral fungal burden and fungal dissemination. Our study reveals that EphA2 functions as PRR for β-glucans that senses epithelial cell fungal burden and is required for the maximal mucosal inflammatory response to C. albicans.One Sentence Summary:EphA2 is a pattern recognition receptor that senses fungal β-glucans to induce an inflammatory response in oral epithelial cells.

scholarly journals Anti-inflammatory effects of olanexidine gluconate on oral epithelial cells

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Takuya Nii ◽  
Hiromichi Yumoto ◽  
Katsuhiko Hirota ◽  
Yoichiro Miyake
Keyword(s):  
Epithelial Cells ◽  
Biofilm Formation ◽  
Inflammatory Responses ◽  
Oral Bacteria ◽  
Dependent Manner ◽  
Chemokine Production ◽  
Oral Epithelial Cells ◽  
Chronic Inflammatory Condition ◽  
Anti Inflammatory ◽  
Oral Epithelial

Abstract Background Periodontitis is a biofilm-induced chronic inflammatory condition of the periodontium. Chemokines produced by the innate and acquired immune responses play a significant role in disease progression. Reducing biofilm formation and inflammatory response caused by chemokines is vital for preventing and treating periodontitis. Previously, we observed that treatment with 0.1% olanexidine gluconate (OLG) inhibited biofilm formation on saliva-coated hydroxyapatite. This study aimed to evaluate the anti-inflammatory effect of OLG on oral epithelial cells. Methods We examined if OLG could inhibit the inflammatory responses caused by Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS) and heat-killed P. gingivalis in immortalized human oral keratinocytes (RT7). Results Treatment of RT7 with non-cytotoxic OLG concentrations significantly inhibited the production of inflammatory chemokines such as interleukin 8 (IL-8), C-C motif ligand 20 (CCL20), and growth-related oncogene protein-α (GRO-α), which are stimulated by P. gingivalis LPS in a concentration-dependent manner. Moreover, the inhibitory effects were observed regardless of the treatment time with P. gingivalis LPS (6, 12, or 24 h). OLG also significantly inhibited chemokine production stimulated by heat-killed P. gingivalis. Conclusions The findings of this study suggest that treatment with OLG inhibits chronic inflammatory reactions in oral mucosal cells, such as periodontitis, caused by oral bacteria.

scholarly journals Semaphorin 4D induces an imbalance of Th17/Treg cells by activating the aryl hydrocarbon receptor in ankylosing spodylitis

2020 ◽  
Author(s):  
Jianmin Xie ◽  
Wang Zitao ◽  
Gu Jieruo
Keyword(s):  
T Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Treg Cells ◽  
Enzyme Linked Immunosorbent Assay ◽  
Dependent Manner ◽  
Semaphorin 4D ◽  
Aryl Hydrocarbon

Abstract Background: Semaphorin 4D (Sema4D) is constitutively expressed on T cells and osteoclasts, and regulates T cell proliferation and bone remodeling. In addition, several studies have shown that Sema4D is involved in the pathogenesis of autoimmunity. We undertook this study to investigate the mechanism by which Sema4D affects the pathogenic progress of ankylosing spondylitis (AS). Methods: Soluble Sema4D (sSema4D) levels in serum were analyzed by enzyme-linked immunosorbent assay. The cell surface levels and transcripts of Sema4D were evaluated in CD4+ and CD19+ cells from the AS patients and healthy individuals. The mRNA expression levels were assessed by quantitative polymerase chain reaction (qPCR). The proportions of Treg cells and IL-17-producing T-cells (Th17 cells) differentiated from CD4+ T cells were analyzed by flow cytometric analysis. The aryl hydrocarbon receptor (AhR) agonistic effect of Sema4D was detected by analyzing the activation of downstream signaling pathways and target genes using Luciferase and EROD assay.Results: Levels of sSema4D were elevated in both serum from AS patients, and clinical features markers were correlated with serum sSema4D levels. Sema4D facilitated CD4+ T cells proliferation and Th17 cells differentiation and inhibited Treg cells differentiation by enhancing RORγt expression and reducing Foxp3 expression, with increasing expression and secretion of IL-17 and IL-22. It induced the expression and activity of AhR target gene CYP1A1 and XRE reporter activity via interaction with CD72. Conclusions: These findings indicate that Sema4D as a potent activator of T cells in the immune response contributes to the inflammation of AS by inducing imbalance in Th17 and Treg cell populations in an AhR-dependent manner, suggesting it is a crucial participant in AS pathogenesis.

Proteolysis of ICAM-1 on Human Oral Epithelial Cells by Gingipains

2003 ◽  
Vol 82 (10) ◽  
pp. 796-801 ◽  
Author(s):  
H. Tada ◽  
S. Sugawara ◽  
E. Nemoto ◽  
T. Imamura ◽  
J. Potempa ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Immune Evasion ◽  
Intercellular Adhesion Molecule ◽  
Dependent Manner ◽  
Intercellular Adhesion Molecule 1 ◽  
Periodontal Tissues ◽  
Oral Epithelial Cells ◽  
Oral Epithelial Cell ◽  
Oral Epithelial

Cysteine proteinases (gingipains) from Porphyromonas gingivalis are considered key virulence factors of severe periodontitis and host immune evasion. Since expression of intercellular adhesion molecule-1 (ICAM-1) on gingival epithelium is indispensable in polymorphonuclear leukocyte (PMN) migration at the site of periodontitis, we examined the effects of gingipains on the expression of ICAM-1 on human oral epithelial cell lines (KB and HSC-2) by flow cytometry and Western blotting. We found that three purified forms of gingipains efficiently reduced ICAM-1 expression on the cells in a time- and dose-dependent manner. Gingipains reduced the expression on fixed cells and degraded the ICAM-1 in the cell membranes, indicating that the reduction resulted from direct proteolysis. They then disturbed the ICAM-1-dependent adhesion of PMNs to the cells. These results indicate that gingipains cleave ICAM-1 on oral epithelial cells, consequently disrupting PMN-oral epithelial cell interaction, and are involved in immune evasion by the bacterium in periodontal tissues.

scholarly journals Dual regulation of interleukin-8 production in human oral epithelial cells upon stimulation with gingipains from Porphyromonas gingivalis

2008 ◽  
Vol 57 (4) ◽  
pp. 500-507 ◽  
Author(s):  
Akiko Uehara ◽  
Mariko Naito ◽  
Takahisa Imamura ◽  
Jan Potempa ◽  
James Travis ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Porphyromonas Gingivalis ◽  
Nuclear Factor Kappa B ◽  
Periodontal Diseases ◽  
Nuclear Factor ◽  
Cysteine Proteinases ◽  
Oral Epithelial Cells ◽  
Cellular Recognition ◽  
Oral Epithelial ◽  
Pro Inflammatory Cytokines

Cysteine proteinases from Porphyromonas gingivalis, or gingipains, are considered to be key virulence factors of the bacterium in relation to periodontal diseases. Incubation of human oral epithelial cells with lysine-specific gingipain (Kgp) and high-molecular-mass arginine-specific gingipain (HRgpA) resulted in a decrease in the production of interleukin (IL)-8, but not in the production of other pro-inflammatory cytokines. In contrast, arginine-specific gingipain 2 (RgpB) increased IL-8 production. RNA interference assays demonstrated that Kgp- and HRgpA-mediated downregulation and RgpB-mediated upregulation occurred through protease-activated receptor (PAR)-1 and PAR-2 signalling. Although the RgpB-mediated upregulation of IL-8 production occurred through nuclear factor-kappa B (NF-κB), the Kgp- and HRgpA-mediated downregulation was not negated in NF-κB-silenced cells. Both the haemagglutinin and the enzymic domains are required for Kgp and HRgpA to downregulate the production of IL-8 in human oral epithelial cells, and the two domains are thought to co-exist. These results suggest that gingipains preferentially suppress IL-8, resulting in attenuation of the cellular recognition of bacteria, and as a consequence, sustain chronic inflammation.

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