All-trans retinoic acid attenuates airway inflammation by inhibiting Th2 and Th17 response in experimental allergic asthma

Wu, Jinhong; Zhang, Yanjie; Liu, Qi; Zhong, Wenxiang; Xia, Zhenwei

doi:10.1186/1471-2172-14-28

Cited by 55 publications

(42 citation statements)

References 37 publications

(38 reference statements)

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“…RA regulates inflammation, cell proliferation and differentiation, tissue development and maintenance, and immune homeostasis, modulating target gene transcription [7,10,19,20]. Its activity is mediated by RXR and RAR receptors.…”

Section: Ra Selectively Stimulates Gene Expression In A549 Cellsmentioning

confidence: 99%

Retinoic Acid Modulates PTGDR Promoter Activity

García-Sánchez

Marcos-Vadillo

Sanz

et al. 2016

J Investig Allergol Clin Immunol

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Background and Objective: Vitamin A has been linked to the development of allergic diseases although its role is not fully understood, Retinoic acid (RA), a metabolite of Vitamin A, has been previously associated with the prostaglandin pathway, and PTGDR, a receptor of PGD2, has been proposed as a candidate gene in allergy and asthma. Considering the role of PTGDR in allergy, the goal of this study was to analyze the effect of RA on the activation of the promoter region of the PTGDR gene. Methods: A549 lung epithelial cells were transfected with 4 combinations of genetic variants of the PTGDR promoter and stimulated with all-trans RA (ATRA); luciferase assays were performed using the Dual Luciferase Reporter System, and real-time quantitative polymerase chain reaction was used to measure the expression of PTGDR, CYP26A1, RARA, RARB, RARG, and RXRA in basal A549 cell cultures and after ATRA treatment. We also performed an in silico analysis. Results: After ATRA treatment increased expression of CYP26A1 (12-fold) and RARB (4-fold) was detected. ATRA activated PTGDR promoter activity in transfected cells (P<.001) and RA response element sequences were identified in silico in this promoter region. Conclusions: RA modulated PTGDR promoter activity. Differential response to RA and to new treatments based on PTGDR modulation could depend on genetic background in allergic asthmatic patients.

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Section: Ra Selectively Stimulates Gene Expression In A549 Cellsmentioning

confidence: 99%

Retinoic Acid Modulates PTGDR Promoter Activity

García-Sánchez

Marcos-Vadillo

Sanz

et al. 2016

J Investig Allergol Clin Immunol

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“…Increased ATRA levels induce IL-4 gene expression in myelin basic protein-specific T cells, which consequently express a Th1-like phenotype (Lovett-Racke and Racke, 2002), while ATRA deficiency has been found to result in an increase in the number of Th1 cells (Nozaki et al, 2006). Retinoic acid has been shown to delay the differentiation and maturation of dendritic cells, reduce the activity of lymphocyte reaction, reduce Thl cytokine production, and increase Th2 cytokines, thereby causing a shift of the immune response to Th2 (Bai et al, 2010;Wansley et al, 2013;Wu et al, 2013;Yokota-Nakatsuma et al, 2014). These observations suggest that ATRA regulates the Th1/Th2 balance by regulating the expression of cytokines, specifically by inhibiting Th1 cell activity and elevating the number of Th2 cells.…”

Section: Discussionmentioning

confidence: 99%

All-trans retinoic acid prevents the development of type 1 diabetes by affecting the levels of interferon gamma and interleukin 4 in streptozotocin-induced murine diabetes model

Wang¹,

Zhong²,

Wang³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to explore the molecular mechanism by which all-trans retinoic acid (ATRA) prevents type 1 diabetes mellitus (T1DM). Fifty ICR mice were randomly assigned to three groups: prevention group [N = 20; mice received 10 mg/kg ATRA daily for 5 days and then 60 mg/kg streptozotocin (STZ) for 5 days]; diabetic group (N = 20, mice received 95% sterile peanut oil and 5% dimethyl sulfoxide for 5 days and then 60 mg/kg STZ for 5 days); and control group (N = 10, mice received 95% sterile peanut oil and 5% dimethyl sulfoxide for 5 days and then citrate buffer for 5 days). Blood glucose was measured using blood glucose test strips and serum insulin was measured by radioimmunoassay. Islets cell morphology was assessed by microscopy and ELISA was used to measure the serum levels of interferon gamma (IFN-γ) and interleukin 4 (IL-4). In the prevention group, blood sugar levels were found to be reduced and serum insulin levels increased compared with the levels in the diabetic group (P < 0.05), indicating that ATRA prevented the STZinduced damage to islet cells. Meanwhile, ATRA was shown to decrease the levels of IFN-γ and increase the levels of IL-4 as well as the IFN-γ/IL-4 ratio in STZ-treated animals (P < 0.05). These findings suggest that ATRA prevents the recurrence of autoimmune insulitis. This study demonstrated that ATRA effectively prevents the progression of T1DM in a murine model of the disease by reducing IFN-γ levels and increasing IL-4 levels.

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“…Maret et al [40] reported that systemic administration of liposome-encapsulated ATRA during the sensitization phase induced more sustained levels of RA (as compared with a conventional ATRA formulation); this augmented airway eosinophilia, the levels of Th2 cytokines and chemokines, and serum IgE levels. On the other hand, systemic administration of ATRA from immunization to the challenge phases ameliorated airway allergic inflammation by modulating Th2 differentiation [41] . In the present study, oral administration of ATRA concomitant to OVA augmented the oral tolerance.…”

Section: Discussionmentioning

confidence: 99%

The Effects of All-Trans Retinoic Acid on the Induction of Oral Tolerance in a Murine Model of Bronchial Asthma

Sakamoto

Koya²,

Tsukioka³

et al. 2015

Int Arch Allergy Immunol

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Background: Active suppression induced by regulatory T (Treg) cells is reported to be one of the mechanisms involved in oral tolerance. All-trans retinoic acid (ATRA) has been reported to affect Treg cell differentiation. The present study examined the effects of ATRA on the induction of oral tolerance in a murine model of bronchial asthma. Methods: BALB/c mice were sensitized to and challenged with ovalbumin (OVA) through feeding followed by OVA challenges. In some study groups ATRA was orally administered concomitantly with OVA feeding either in the presence or absence of the retinoic acid receptor antagonist LE135. Lung CD4⁺ T cells were isolated from mice exposed to ATRA and/or OVA, and transferred to control mice. Airway hyperresponsiveness (AHR), cell counts and cytokine levels in bronchoalveolar lavage (BAL) fluid, and lung histology were assessed. Results: Concomitant administration of ATRA with OVA ameliorated AHR, airway eosinophilia, elevation of cytokines in BAL fluid and goblet cell metaplasia. The proportion of Treg cells in the lungs was increased in mice treated with OVA and ATRA, as compared to those treated with OVA only. Transfer of lung CD4⁺ T cells from mice treated with OVA and ATRA induced suppression of AHR and airway inflammation. LE135 completely reversed the effects of ATRA on AHR, airway allergic inflammation and the number of Treg cells in the lungs. Conclusion: These data suggested that oral administration of ATRA with OVA had the potential to enhance oral tolerance in this murine model of bronchial asthma. These effects were mediated, at least in part, by Treg cell expansion.

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All-trans retinoic acid attenuates airway inflammation by inhibiting Th2 and Th17 response in experimental allergic asthma

Cited by 55 publications

References 37 publications

Retinoic Acid Modulates PTGDR Promoter Activity

Retinoic Acid Modulates PTGDR Promoter Activity

All-trans retinoic acid prevents the development of type 1 diabetes by affecting the levels of interferon gamma and interleukin 4 in streptozotocin-induced murine diabetes model

The Effects of All-Trans Retinoic Acid on the Induction of Oral Tolerance in a Murine Model of Bronchial Asthma

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