Suppression of ovalbumin-induced Th2-driven airway inflammation by β-sitosterol in a guinea pig model of asthma

Mahajan, Shailaja G.; Mehta, Abhishek

doi:10.1016/j.ejphar.2010.09.075

Cited by 84 publications

(56 citation statements)

References 26 publications

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“…Rat and guinea pig models of asthma have the classic Th2 asthmatic phenotype, which is characterized by high levels of antigenspecific IgE, eosinophil-dominated airway inflammation, and a pattern of Th2 cytokines including IL-4, IL-5, and IL-13 (32)(33)(34). In our studies, we found that treatment of BSMCs with serum from patients with asthma induced FKBP12.6 down-regulation and decreased association of FKBP12.6 from RyR2.…”

Section: Discussionsupporting

confidence: 49%

Dissociation of FK506-Binding Protein 12.6 kD from Ryanodine Receptor in Bronchial Smooth Muscle Cells in Airway Hyperresponsiveness in Asthma

Du¹,

Zhao²,

Li³

et al. 2014

Am J Respir Cell Mol Biol

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Airway hyperresponsiveness (AHR) in asthma is predominantly caused by increased sensitivity of bronchial smooth muscle cells (BSMCs) to stimuli. The sarcoplasmic reticulum (SR)-Ca 21 release channel, known as ryanodine receptor (RyR), mediates the contractive response of BSMCs to stimuli. FK506-binding protein 12.6 kD (FKBP12.6) stabilizes the RyR2 channel in a closed state. However, the interaction of FKBP12.6 with RyR2 in AHR remains unknown. This study examined the interaction of FKBP12.6 with RyR2 in BSMCs in AHR of asthma. The interaction of FKBP12.6 with RyR2 and FKBP12.6 expression was determined in a rat asthma model and in BSMCs treated with inflammatory cytokines. The calcium responses to contractile agonists were determined in BSMCs with overexpression and knockdown of FKBP12.6. Asthmatic serum, IL-5, IL-13, and TNF-a enhance the calcium response of BSMCs to contractile agonists and cause dissociation of FKBP12.6 from RyR2 and a decrease in FKBP12.6 gene expression in BSMCs in culture and in ovalbumin (OVA)-sensitized and -challenged rats. Knockdown of FKBP12.6 in BSMCs causes a decrease in the association of RyR2 with FKBP12.6 and an increase in the calcium response of BSMCs. Overexpression of FKBP12.6 increases the association of FKBP12.6 with RyR2, decreases the calcium response of BSMCs, and normalizes airway responsiveness in OVA-sensitized and -challenged rats. Dissociation of FKBP12.6 from RyR2 in BSMCs is responsible for the increased calcium response contributing to AHR in asthma. Manipulating the interaction of FKBP12.6 with RyR2 might be a novel and useful treatment for asthma.Keywords: asthma; airway hyperresponsiveness; calcium; RyR2; FKBP12.6 Clinical RelevanceAlthough enhanced calcium response of bronchial smooth muscle to stimuli has been reported to be involved in asthmatic airway hyperresponsiveness, an interaction of FKBP12.6 with RyR2 on sarcoplasmic reticulum in asthmatic airway hyperresponsiveness has not been investigated. We have shown that increased responsiveness of bronchial smooth muscle in asthma is attributed to the dissociation of FKBP12.6 from ryanodine receptor 2, which promotes calcium release from the sarcoplasmic reticulum.

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Section: Discussionsupporting

confidence: 49%

Dissociation of FK506-Binding Protein 12.6 kD from Ryanodine Receptor in Bronchial Smooth Muscle Cells in Airway Hyperresponsiveness in Asthma

Du¹,

Zhao²,

Li³

et al. 2014

Am J Respir Cell Mol Biol

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“…Also, blocking the Il13 receptor improved asthma in CAB/J mice [11], indicating the pathologic role of this specific Th2 cytokine [32]. Very recently, it has been shown that beta-sitosterol has the ability to reduce airway inflammation in an asthma model in guinea pigs [33]. Fully in line with this finding, we here show that sitostanol induced a Th1 response in PBMCs from asthma patients, indicated by an increase in the concentration of cytokines IL-2 and IFNγ.…”

Section: Discussionmentioning

confidence: 98%

Beneficial Effects of Sitostanol on the Attenuated Immune Function in Asthma Patients: Results of an In Vitro Approach

et al. 2012

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BackgroundIn vitro and animal studies have suggested that plant sterols and stanols increase cytokine production by T-helper-1 cells. This may be beneficial for patient groups characterized by a T-helper-2 dominant immune response, e.g. asthma patients. (1) to evaluate whether sitostanol induces a T-helper-1 shift in peripheral blood mononuclear cells (PBMCs) from asthma patients, and (2) to unravel the role of regulatory T-cells in this respect.Methodology/Principal FindingsPBMCs from 10 asthma patients and 10 healthy subjects were isolated and incubated with 1.2 µM sitostanol, while stimulated with 5 µg/ml PHA. Similar amounts of cholesterol were used to determine whether effects were specific for plant stanols or for sterols in general. Changes in cytokine production were measured using antibody arrays and ELISAs. Changes in regulatory T-cell population size were measured by flow cytometry, using intracellular Foxp3 staining. Sitostanol increased production of IFNγ by 6.5% and IL-2 by 6.0% compared to cholesterol (p<0.01). No changes in IL-4 and IL-13 were found. Interestingly, this effect was only present in PBMCs from asthma patients. The number of Foxp3+ cells tended to increase and their activity, measured by IL-10 production, increased after sitostanol treatment in PBMCs from asthma patients compared to controls by 32.3% (p = 0.077) and 13.3% (p<0.05), respectively.Conclusions/SignificanceAltogether, the sitostanol-induced Thelper-1 shift in PBMCs from asthma patients and the stimulating effects of sitostanol on Treg cell numbers and activity indicate a possible novel approach for plant stanol ester enriched functional foods in the amelioration of asthmatic symptoms. Functional effects, however, require further evaluation.

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“…Aucubin inhibits 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema and production of TNF-␣ and IL-6 in mast cells (Recio et al, 1994;Jeong et al, 2002). Recently, it has been reported that betasitosterol, one of the major constituents of Rehmannia glutinosa (Ni et al, 1992), inhibits ovalbumin-induced airway inflammation in a guinea pig asthma model (Mahajan and Mehta, 2011). These results suggest that Rehmannia glutinosa might be beneficial in the treatment of human allergic disorders.…”

Section: Introductionmentioning

confidence: 95%

Topical application of Rehmannia glutinosa extract inhibits mite allergen-induced atopic dermatitis in NC/Nga mice

Sung

Yoon

Jang

et al. 2011

Journal of Ethnopharmacology

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Suppression of ovalbumin-induced Th2-driven airway inflammation by β-sitosterol in a guinea pig model of asthma

Cited by 84 publications

References 26 publications

Dissociation of FK506-Binding Protein 12.6 kD from Ryanodine Receptor in Bronchial Smooth Muscle Cells in Airway Hyperresponsiveness in Asthma

Dissociation of FK506-Binding Protein 12.6 kD from Ryanodine Receptor in Bronchial Smooth Muscle Cells in Airway Hyperresponsiveness in Asthma

Beneficial Effects of Sitostanol on the Attenuated Immune Function in Asthma Patients: Results of an In Vitro Approach

Topical application of Rehmannia glutinosa extract inhibits mite allergen-induced atopic dermatitis in NC/Nga mice

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