scholarly journals Hydroquinone Exposure Worsens Rheumatoid Arthritis through the Activation of the Aryl Hydrocarbon Receptor and Interleukin-17 Pathways

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 929
Author(s):  
Cintia Scucuglia Heluany ◽  
Paula Barbim Donate ◽  
Ayda Henriques Schneider ◽  
André Luis Fabris ◽  
Renan Augusto Gomes ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Gene Expression ◽  
Aryl Hydrocarbon Receptor ◽  
Cigarette Smoke ◽  
Cigarette Smoke Exposure ◽  
Interleukin 17 ◽  
Aryl Hydrocarbon ◽  
Tnf Α

Rheumatoid arthritis (RA) development is strongly associated with cigarette smoke exposure, which activates the aryl hydrocarbon receptor (AhR) as a trigger for Th17 inflammatory pathways. We previously demonstrated that the exposure to hydroquinone (HQ), one of the major compounds of cigarette tar, aggravates the arthritis symptomatology in rats. However, the mechanisms related to the HQ-related RA still remain elusive. Cell viability, cytokine secretion, and gene expression were measured in RA human fibroblast-like synoviocytes (RAHFLS) treated with HQ and stimulated or not with TNF-α. Antigen-induced arthritis (AIA) was also elicited in wild type (WT), AhR −/− or IL-17R −/− C57BL/6 mice upon daily exposure to nebulized HQ (25ppm) between days 15 to 21. At day 21, mice were challenged with mBSA and inflammatory parameters were assessed. The in vitro HQ treatment up-regulated TNFR1, TNFR2 expression, and increased ROS production. The co-treatment of HQ and TNF-α enhanced the IL-6 and IL-8 secretion. However, the pre-incubation of RAHFLS with an AhR antagonist inhibited the HQ-mediated cell proliferation and gene expression profile. About the in vivo approach, the HQ exposure worsened the AIA symptoms (edema, pain, cytokines secretion and NETs formation) in WT mice. These AIA effects were abolished in HQ-exposed AhR −/− and IL-17R −/− animals though. Our data demonstrated the harmful HQ influence over the onset of arthritis through the activation and proliferation of synoviocytes. The HQ-related RA severity was also associated with the activation of AhR and IL-17 pathways, highlighting how cigarette smoke compounds can contribute to the RA progression.

scholarly journals Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol

2000 ◽  
Vol 167 (1) ◽  
pp. 183-195 ◽  
Author(s):  
SU Singh ◽  
RF Casper ◽  
PC Fritz ◽  
B Sukhu ◽  
B Ganss ◽  
...  
Keyword(s):  
Periodontal Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Cigarette Smoke ◽  
Bone Cell ◽  
Nodule Formation ◽  
Antifungal Compound ◽  
Type I ◽  
Aryl Hydrocarbon

Aryl hydrocarbon receptor (AhR) ligands are environmental contaminants found in cigarette smoke and other sources of air pollution. The prototypical compound is TCDD (2,3,7, 8-tetrachlorodibenzo-p-dioxin), also known as dioxin. There is an increasing body of knowledge linking cigarette smoking to osteoporosis and periodontal disease, but the direct effects of smoke-associated aryl hydrocarbons on bone are not well understood. Through the use of resveratrol (3,5,4'-trihydroxystilbene), a plant antifungal compound that we have recently demonstrated to be a pure AhR antagonist, we have investigated the effects of TCDD on osteogenesis. It was postulated that TCDD would inhibit osteogenesis in bone-forming cultures and that this inhibition would be antagonized by resveratrol. We employed the chicken periosteal osteogenesis (CPO) model, which has been shown to form bone in vitro in a pattern morphologically and biochemically similar to that seen in vivo, as well as a rat stromal cell bone nodule formation model. In the CPO model, alkaline phosphatase (AP) activity was reduced by up to 50% (P<0.01 vs control) in the presence of 10(-9) M TCDD and these effects were reversed by 10(-6) M resveratrol (P<0.05 vs TCDD alone). TCDD-mediated inhibition of osteogenesis was restricted primarily to the osteoblastic differentiation phase (days 0-2) as later addition did not appear to have any effects. Message levels for important bone-associated proteins (in the CPO model) such as collagen type I, osteopontin, bone sialoprotein and AP were inhibited by TCDD, an effect that was antagonized by resveratrol. Similar findings were obtained using the rat stromal bone cell line. TCDD (at concentrations as low as 10(-10)M) caused an approximately 33% reduction in AP activity, which was abrogated by 3. 5x10(-7) M resveratrol. TCDD also induced a marked reduction in mineralization ( approximately 75%) which was completely antagonized by resveratrol. These data suggest that AhR ligands inhibit osteogenesis probably through inhibition of osteodifferentiation and that this effect can be antagonized by resveratrol. Since high levels of AhR ligands are found in cigarette smoke, and further since smoking is an important risk factor in both osteoporosis and periodontal disease, it may be postulated that AhR ligands are the component of cigarette smoke linking smoking to osteoporosis and periodontal disease. If so, resveratrol could prove to be a promising preventive or therapeutic agent for smoking-related bone loss.

scholarly journals Modulatory Effects of Osthole on Lipopolysaccharides-Induced Inflammation in Caco-2 Cell Monolayer and Co-Cultures with THP-1 and THP-1-Derived Macrophages

Nutrients ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 123
Author(s):  
Natalia K. Kordulewska ◽  
Justyna Topa ◽  
Małgorzata Tańska ◽  
Anna Cieślińska ◽  
Ewa Fiedorowicz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Reaction ◽  
Wide Spectrum ◽  
Cell Monolayer ◽  
In Vivo Studies ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Tnf Α

Lipopolysaccharydes (LPS) are responsible for the intestinal inflammatory reaction, as they may disrupt tight junctions and induce cytokines (CKs) secretion. Osthole has a wide spectrum of pharmacological effects, thus its anti-inflammatory potential in the LPS-treated Caco-2 cell line as well as in Caco-2/THP-1 and Caco-2/macrophages co-cultures was investigated. In brief, Caco-2 cells and co-cultures were incubated with LPS to induce an inflammatory reaction, after which osthole (150–450 ng/mL) was applied to reduce this effect. After 24 h, the level of secreted CKs and changes in gene expression were examined. LPS significantly increased the levels of IL-1β, -6, -8, and TNF-α, while osthole reduced this effect in a concentration-dependent manner, with the most significant decrease when a 450 ng/mL dose was applied (p < 0.0001). A similar trend was observed in changes in gene expression, with the significant osthole efficiency at a concentration of 450 ng/μL for IL1R1 and COX-2 (p < 0.01) and 300 ng/μL for NF-κB (p < 0.001). Osthole increased Caco-2 monolayer permeability, thus if it would ever be considered as a potential drug for minimizing intestinal inflammatory symptoms, its safety should be confirmed in extended in vitro and in vivo studies.

scholarly journals Mouse Protocadherin-1 Gene Expression Is Regulated by Cigarette Smoke Exposure In Vivo

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e98197 ◽  
Author(s):  
Henk Koning ◽  
Antoon J. M. van Oosterhout ◽  
Uilke Brouwer ◽  
Lisette E. den Boef ◽  
Renée Gras ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Exposure In Vivo

scholarly journals Increase Paclitaxel Sensitivity to Better Suppress Serous Epithelial Ovarian Cancer via Ablating Androgen Receptor/Aryl Hydrocarbon Receptor-ABCG2 Axis

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 463 ◽  
Author(s):  
Wei-Min Chung ◽  
Yen-Ping Ho ◽  
Wei-Chun Chang ◽  
Yuan-Chang Dai ◽  
Lumin Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Androgen Receptor ◽  
Epithelial Ovarian Cancer ◽  
Aryl Hydrocarbon Receptor ◽  
Proximal Promoter ◽  
Luciferase Reporter ◽  
Aryl Hydrocarbon ◽  
Paclitaxel Treatment

Background: Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies and presents chemoresistance after chemotherapy treatment. Androgen receptor (AR) has been known to participate in proliferation. Yet the mechanisms of the resistance of this drug and its linkage to the AR remains unclear. Methods: To elucidate AR-related paclitaxel sensitivity, co-IP, luciferase reporter assay and ChIP assay were performed to identify that AR direct-regulated ABCG2 expression under paclitaxel treatment. IHC staining by AR antibody presented higher AR expression in serous-type patients than other types. AR degradation enhancer (ASC-J9) was used to examine paclitaxel-associated and paclitaxel-resistant cytotoxicity in vitro and in vivo. Results: We found AR/aryl hydrocarbon receptor (AhR)-mediates ABCG2 expression and leads to a change in paclitaxel cytotoxicity/sensitivity in EOC serous subtype cell lines. Molecular mechanism study showed that paclitaxel activated AR transactivity and bound to alternative ARE in the ABCG2 proximal promoter region. To identify AR as a potential therapeutic target, the ASC-J9 was used to re-sensitize paclitaxel-resistant EOC tumors upon paclitaxel treatment in vitro and in vivo. Conclusion: The results demonstrated that activation of AR transactivity beyond the androgen-associated biological effect. This novel AR mechanism explains that degradation of AR is the most effective therapeutic strategy for treating AR-positive EOC serous subtype.

scholarly journals The aryl hydrocarbon receptor is a novel negative regulator of interleukin‐17‐mediated signaling and inflammation in vitro

FEBS Letters ◽  
2019 ◽  
Vol 593 (9) ◽  
pp. 952-961
Author(s):  
Hui Li ◽  
Wei Hong ◽  
Xiangyu Jin ◽  
Guangliang Li ◽  
Guoming Zhou ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Negative Regulator ◽  
Interleukin 17 ◽  
Aryl Hydrocarbon

Humic-like substances in cigarette smoke condensate and lung tissue of smokers

1994 ◽  
Vol 266 (4) ◽  
pp. L382-L388 ◽  
Author(s):  
A. J. Ghio ◽  
J. Stonehuerner ◽  
D. R. Quigley
Keyword(s):  
Free Radical ◽  
Cigarette Smoke ◽  
Lung Tissue ◽  
Cigarette Smoke Exposure ◽  
Cigarette Smoke Condensate ◽  
Free Radical Generation ◽  
Carboxylate Content ◽  
Radical Generation

Deposition of pigmented matter in the lower respiratory tract correlates with the extent of emphysema in smokers as well as with free radical generation and iron accumulation. Pulmonary emphysema is postulated to be mediated by free radical generation which is either directly or indirectly associated with cigarette smoke exposure. The hypothesis was tested that 1) incomplete combustion of tobacco yields humic-like substances (HLS) which 2) deposit in the lung as pigmented particulates, 3) complex iron cations in vitro and in vivo, and 4) have a capacity to catalyze oxidant formation. HLS, isolated by alkali extraction of cigarette smoke condensate (CSC) (Tobacco Health Research Institute, University of Kentucky), demonstrated a high carbon and low carboxylate content on elemental and functional group analyses, respectively, compared with values for HLS sequestered from soils. The HLS isolated from CSC had a capacity to complex iron in vitro and accumulated the metal in vivo after intratracheal instillation in an animal model. Both HLS and its iron complex generated free radicals, and some portion of this oxidant generation was metal dependent. Lung tissue collected at autopsy from smokers contained HLS with an infrared spectrum almost identical to that of the material isolated from CSC. Associations between particulate deposition, metal accumulation, and free radical generation suggest a possible role of HLS in the induction of lung disease following cigarette exposure.

scholarly journals Aryl hydrocarbon receptor (AhR)-dependent regulation of pulmonary miRNA by chronic cigarette smoke exposure

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Sarah Rogers ◽  
Angela Rico de Souza ◽  
Michela Zago ◽  
Matthew Iu ◽  
Necola Guerrina ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Aryl Hydrocarbon

scholarly journals Disruption of endogenous regulator homeostasis underlies the mechanism of rat CYP1A1 mRNA induction by metyrapone

1998 ◽  
Vol 331 (1) ◽  
pp. 273-281 ◽  
Author(s):  
Joanna L. HARVEY ◽  
Alan J. PAINE ◽  
Matthew C. WRIGHT
Keyword(s):  
Gene Expression ◽  
Glucocorticoid Receptor ◽  
Aryl Hydrocarbon Receptor ◽  
Culture Medium ◽  
Male Rats ◽  
Aryl Hydrocarbon ◽  
Mrna Induction ◽  
Cyp1a1 Gene ◽  
Cyp1a1 Mrna

The transcriptional induction of the cytochrome P-450 1A1 (CYP1A1) gene by xenobiotics such as polyaromatic hydrocarbons is dependent on their interaction with the aryl hydrocarbon receptor. Administration of the structurally unrelated compounds metyrapone (a cytochrome P-450 inhibitor) or dexamethasone (a glucocorticoid) to male rats does not induce hepatic CYP1A1 mRNA. However, administration of both metyrapone and dexamethasone to male rats results in the induction of hepatic CYP1A1 mRNA expression. The induction response is mimicked in vitro in cultured rat hepatocytes by the addition of metyrapone and dexamethasone to a serum-free culture medium, suggesting that these compounds act directly on the liver in vivo to effect hepatic CYP1A1 mRNA induction. An examination of the characteristics of CYP1A1 induction by metyrapone and dexamethasone in combination in vitro indicate that at least 6 h of treatment is required for detectable levels of CYP1A1 mRNA to accumulate in hepatocytes. In contrast, β-naphthoflavone, which is known to bind to the aryl hydrocarbon receptor to effect CYP1A1 gene expression, induces detectable levels of CYP1A1 mRNA within 2 h of treatment. CYP1A1 mRNA is also induced when hepatocytes are treated with metyrapone in combination with the protein synthesis inhibitor cycloheximide but not with dexamethasone in combination with cycloheximide, indicating that CYP1A1 mRNA induction is strictly dependent on the presence of metyrapone and suggesting that the metyrapone-associated induction of CYP1A1 mRNA is dependent on a loss of a constitutively expressed protein that functions to suppress CYP1A1 gene expression. The role of dexamethasone in metyrapone-associated induction of CYP1A1 is probably mediated through the glucocorticoid receptor since the glucocorticoid receptor antagonist RU486 reduces the levels of CYP1A1 mRNA induced by metyrapone and dexamethasone in combination. Increasing the levels of the photosensitizer riboflavin present in the culture medium 10-fold and exposure to light increases the levels of CYP1A1 mRNA induced by metyrapone and dexamethasone in combination in vitro, suggesting that photoactivation of inducing medium constituent(s) might be required for induction. Failure to induce CYP1A1 mRNA by co-administration of metyrapone and dexamethasone in hepatocytes cultured in a balanced salt solution with or without photoactivation indicates that induction is dependent on a photoactivated component of the culture medium and not on metyrapone or dexamethasone alone. The addition of tryptophan in the presence of riboflavin to the balanced salt solution restores CYP1A1 mRNA induction by metyrapone alone and induction is increased when medium is exposed to light, indicating that induction is dependent on tryptophan photoactivation in vitro. Metyrapone failed to compete with 2,3,7,8-tetrachlorodibenzo-p-dioxin for specific binding to the aryl hydrocarbon receptor in rat liver cytosolic fractions. These results suggest that CYP1A1 might be induced in rats by metyrapone through an indirect mechanism associated with an elevation in the level of an endogenously generated inducer such as photoactivated product(s) of tryptophan and not because of metyrapone's interacting with the aryl hydrocarbon receptor. The dependence of CYP1A1 induction on dexamethasone or cycloheximide suggests that derepression by a glucocorticoid receptor-modulated negative-acting factor of CYP1A1 gene expression might be critical to induction by metyrapone.

scholarly journals Plasma Levels of Eicosapentaenoic Acid Are Associated with Anti-TNF Responsiveness in Rheumatoid Arthritis and Inhibit the Etanercept-driven Rise in Th17 Cell Differentiationin Vitro

2017 ◽  
Vol 44 (6) ◽  
pp. 748-756 ◽  
Author(s):  
Louisa Jeffery ◽  
Helena L. Fisk ◽  
Philip C. Calder ◽  
Andrew Filer ◽  
Karim Raza ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Fatty Acid ◽  
Eicosapentaenoic Acid ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Differentiationin Vitro

Objective.To determine whether levels of plasma n-3 polyunsaturated fatty acids are associated with response to antitumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA), and whether this putative effect may have its basis in altering anti-TNF–driven Th17 cell differentiation.Methods.Plasma was collected at baseline and after 3 months of anti-TNF treatment in 22 patients with established RA, and fatty acid composition of the phosphatidylcholine (PC) component was measured. CD4+CD25− T cells and monocytes were purified from the blood of healthy donors and cocultured in the presence of anti-CD3, with or without etanercept (ETN), eicosapentaenoic acid (EPA), or the control fatty acid, linoleic acid (LA). Expression of interleukin 17 and interferon-γ was measured by intracellular staining and flow cytometry.Results.Plasma PC EPA levels and the EPA/arachidonic acid ratio correlated inversely with change in the Disease Activity Score at 28 joints (DAS28) at 3 months (−0.51, p = 0.007 and −0.48, p = 0.01, respectively), indicating that higher plasma EPA was associated with a greater reduction in DAS28. Plasma PC EPA was positively associated with European League Against Rheumatism response (p = 0.02). An increase in Th17 cells post-therapy has been associated with nonresponse to anti-TNF. ETN increased Th17 frequenciesin vitro. Physiological concentrations of EPA, but not LA, prevented this.Conclusion.EPA status was associated with clinical improvements to anti-TNF therapyin vivoand prevented the effect of ETN on Th17 cellsin vitro. EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.

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