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Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD.

Chiba T, Chihara J, Furue M - J Allergy (Cairo) (2012)

Bottom Line: The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses.In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD.In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.

ABSTRACT
The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses. These environmental toxicants are known to cause lung cancer but have also recently been implicated in allergic and inflammatory diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD. We have previously reported that human bronchial epithelial cells express AhR, and AhR activation induces mucin production through reactive oxygen species. This review discusses the role of AhR in asthma and COPD, focusing in particular on inflammatory and resident cells in the lung. We describe the important impact that AhR activation may have on the inflammation phase in the pathology of asthma and COPD. In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented.

No MeSH data available.


Related in: MedlinePlus

(a) Effect of PPARγ agonist troglitazone on eosinophil chemotaxis stimulated with eotaxin. Purified eosinophils were preincubated with increasing concentrations of troglitazone for 1 h. Migration assays were performed using Boyden chambers. Chemotactic response to eotaxin alone was considered to be 100%, and reactions to lower concentrations are presented relative to eotaxin alone. Data are expressed as mean ± SD. Troglitazone inhibited the eotaxin-directed eosinophil chemotaxis in a dose-dependent manner (n = 4). *P < 0.05 versus eotaxin alone. (b) Effect of troglitazone on eosinophil survival determined by staining with Annexin V-FITC and propidium iodine. Eosinophils were incubated with and without troglitazone in the presence of 1 ng/mL IL-5 for 48 h. Eosinophils were treated with Annexin V to stain early-phase apoptotic cells and with propidium iodine (PI) to stain the late-phase cells. The bar graph shows a dose-dependent effect of troglitazone on IL-5-induced eosinophil survival (n = 4). Data are expressed as mean ± SD. *P < 0.05 versus without troglitazone.
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fig4: (a) Effect of PPARγ agonist troglitazone on eosinophil chemotaxis stimulated with eotaxin. Purified eosinophils were preincubated with increasing concentrations of troglitazone for 1 h. Migration assays were performed using Boyden chambers. Chemotactic response to eotaxin alone was considered to be 100%, and reactions to lower concentrations are presented relative to eotaxin alone. Data are expressed as mean ± SD. Troglitazone inhibited the eotaxin-directed eosinophil chemotaxis in a dose-dependent manner (n = 4). *P < 0.05 versus eotaxin alone. (b) Effect of troglitazone on eosinophil survival determined by staining with Annexin V-FITC and propidium iodine. Eosinophils were incubated with and without troglitazone in the presence of 1 ng/mL IL-5 for 48 h. Eosinophils were treated with Annexin V to stain early-phase apoptotic cells and with propidium iodine (PI) to stain the late-phase cells. The bar graph shows a dose-dependent effect of troglitazone on IL-5-induced eosinophil survival (n = 4). Data are expressed as mean ± SD. *P < 0.05 versus without troglitazone.

Mentions: Eosinophils play an essential role in the pathology of asthma because they contribute to tissue injury, vascular leakage, mucus secretion, and tissue remodeling by releasing cytotoxic granule proteins, ROS, and lipid mediators [48]. Because eosinophils are the final effector cells in allergic inflammation, it is important to study the process by which nuclear receptors, such as AhR, activate eosinophils in order to understand the pathogenesis of allergic diseases. For example, PPARs are among the important ligand-activated transcription factors that regulate the expression of genes involved in many cellular functions, including differentiation, immune responses, and inflammation [49, 50]. The PPAR subfamily consists of 3 isotypes: PPARα, PPARβ/δ, and PPARγ, all of which have been identified in eosinophils. These nuclear receptors form heterodimers with retinoid X receptors, bind to a specific DNA sequence (PPRE), and activate target gene transcription. In vivo and in vitro evidence suggests that PPARα and PPARγ expression in granulocytes and dendritic cells plays a critical role as an inflammatory suppressive regulator in allergic diseases. Treatment with the PPARγ agonist, rosiglitazone, decreases the clinical severity of skin lesions in atopic dermatitis and airway inflammation in asthmatic patients [51, 52]. We previously demonstrated that the PPARγ agonist troglitazone reduced IL-5-stimulated eosinophil survival, eotaxin-directed eosinophil chemotaxis, and functional augmentation of eosinophil adhesion in a concentration-dependent manner. These changes occurred without reducing the quantitative expression of β2 integrins [53, 54] (Figure 4). It has been lately shown that PPARγ induction is suppressed during the activation of the AhR by TCDD [55]. In addition, Cho et al. demonstrated that CYP1B1 upregulation induced the inhibition of AhR expression in 10T1/2 cells derived from preadipocyte lines. Moreover, the reduced AhR expression was accompanied by an increase in PPARγ expression [56]. These results suggest that the AhR signal may repress migration, degranulation, and cellular adhesion of eosinophils. This may impair the antiallergic effects induced by PPARγ. We were able to confirm AhR expression in human eosinophils using RT-PCR (data not shown). Clarification of the interaction between AhR and PPARγ signals should broaden our understanding not only of the functional role of eosinophils but also of asthma regulation.


Role of the Arylhydrocarbon Receptor (AhR) in the Pathology of Asthma and COPD.

Chiba T, Chihara J, Furue M - J Allergy (Cairo) (2012)

(a) Effect of PPARγ agonist troglitazone on eosinophil chemotaxis stimulated with eotaxin. Purified eosinophils were preincubated with increasing concentrations of troglitazone for 1 h. Migration assays were performed using Boyden chambers. Chemotactic response to eotaxin alone was considered to be 100%, and reactions to lower concentrations are presented relative to eotaxin alone. Data are expressed as mean ± SD. Troglitazone inhibited the eotaxin-directed eosinophil chemotaxis in a dose-dependent manner (n = 4). *P < 0.05 versus eotaxin alone. (b) Effect of troglitazone on eosinophil survival determined by staining with Annexin V-FITC and propidium iodine. Eosinophils were incubated with and without troglitazone in the presence of 1 ng/mL IL-5 for 48 h. Eosinophils were treated with Annexin V to stain early-phase apoptotic cells and with propidium iodine (PI) to stain the late-phase cells. The bar graph shows a dose-dependent effect of troglitazone on IL-5-induced eosinophil survival (n = 4). Data are expressed as mean ± SD. *P < 0.05 versus without troglitazone.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig4: (a) Effect of PPARγ agonist troglitazone on eosinophil chemotaxis stimulated with eotaxin. Purified eosinophils were preincubated with increasing concentrations of troglitazone for 1 h. Migration assays were performed using Boyden chambers. Chemotactic response to eotaxin alone was considered to be 100%, and reactions to lower concentrations are presented relative to eotaxin alone. Data are expressed as mean ± SD. Troglitazone inhibited the eotaxin-directed eosinophil chemotaxis in a dose-dependent manner (n = 4). *P < 0.05 versus eotaxin alone. (b) Effect of troglitazone on eosinophil survival determined by staining with Annexin V-FITC and propidium iodine. Eosinophils were incubated with and without troglitazone in the presence of 1 ng/mL IL-5 for 48 h. Eosinophils were treated with Annexin V to stain early-phase apoptotic cells and with propidium iodine (PI) to stain the late-phase cells. The bar graph shows a dose-dependent effect of troglitazone on IL-5-induced eosinophil survival (n = 4). Data are expressed as mean ± SD. *P < 0.05 versus without troglitazone.
Mentions: Eosinophils play an essential role in the pathology of asthma because they contribute to tissue injury, vascular leakage, mucus secretion, and tissue remodeling by releasing cytotoxic granule proteins, ROS, and lipid mediators [48]. Because eosinophils are the final effector cells in allergic inflammation, it is important to study the process by which nuclear receptors, such as AhR, activate eosinophils in order to understand the pathogenesis of allergic diseases. For example, PPARs are among the important ligand-activated transcription factors that regulate the expression of genes involved in many cellular functions, including differentiation, immune responses, and inflammation [49, 50]. The PPAR subfamily consists of 3 isotypes: PPARα, PPARβ/δ, and PPARγ, all of which have been identified in eosinophils. These nuclear receptors form heterodimers with retinoid X receptors, bind to a specific DNA sequence (PPRE), and activate target gene transcription. In vivo and in vitro evidence suggests that PPARα and PPARγ expression in granulocytes and dendritic cells plays a critical role as an inflammatory suppressive regulator in allergic diseases. Treatment with the PPARγ agonist, rosiglitazone, decreases the clinical severity of skin lesions in atopic dermatitis and airway inflammation in asthmatic patients [51, 52]. We previously demonstrated that the PPARγ agonist troglitazone reduced IL-5-stimulated eosinophil survival, eotaxin-directed eosinophil chemotaxis, and functional augmentation of eosinophil adhesion in a concentration-dependent manner. These changes occurred without reducing the quantitative expression of β2 integrins [53, 54] (Figure 4). It has been lately shown that PPARγ induction is suppressed during the activation of the AhR by TCDD [55]. In addition, Cho et al. demonstrated that CYP1B1 upregulation induced the inhibition of AhR expression in 10T1/2 cells derived from preadipocyte lines. Moreover, the reduced AhR expression was accompanied by an increase in PPARγ expression [56]. These results suggest that the AhR signal may repress migration, degranulation, and cellular adhesion of eosinophils. This may impair the antiallergic effects induced by PPARγ. We were able to confirm AhR expression in human eosinophils using RT-PCR (data not shown). Clarification of the interaction between AhR and PPARγ signals should broaden our understanding not only of the functional role of eosinophils but also of asthma regulation.

Bottom Line: The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses.In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD.In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented.

View Article: PubMed Central - PubMed

Affiliation: Department of Dermatology, Graduate School of Medical Sciences, Kyushu University School of Medicine, 3-1-1, Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.

ABSTRACT
The dioxins and dioxin-like compounds in cigarette smoke and environmental pollutants modulate immunological responses. These environmental toxicants are known to cause lung cancer but have also recently been implicated in allergic and inflammatory diseases such as bronchitis, asthma, and chronic obstructive pulmonary disease (COPD). In a novel pathway of this response, the activation of a nuclear receptor, arylhydrocarbon receptor (AhR), mediates the effects of these toxins through the arachidonic acid cascade, cell differentiation, cell-cell adhesion interactions, cytokine expression, and mucin production that are implicated in the pathogenesis and exacerbation of asthma/COPD. We have previously reported that human bronchial epithelial cells express AhR, and AhR activation induces mucin production through reactive oxygen species. This review discusses the role of AhR in asthma and COPD, focusing in particular on inflammatory and resident cells in the lung. We describe the important impact that AhR activation may have on the inflammation phase in the pathology of asthma and COPD. In addition, crosstalk of AhR signaling with other ligand-activated transcription factors such as peroxisome proliferator-activated receptors (PPARs) has been well documented.

No MeSH data available.


Related in: MedlinePlus