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G-protein-coupled estrogen receptor agonist suppresses airway inflammation in a mouse model of asthma through IL-10.

Itoga M, Konno Y, Moritoki Y, Saito Y, Ito W, Tamaki M, Kobayashi Y, Kayaba H, Kikuchi Y, Chihara J, Takeda M, Ueki S, Hirokawa M - PLoS ONE (2015)

Bottom Line: Although GPER is associated with immunoregulatory functions of estrogen, the pathophysiological role of GPER in allergic inflammatory lung disease has not been examined.G-1 treatment also decreased serum levels of anti-OVA IgE antibodies.The current results have potential importance for understanding the mechanistic aspects of function of estrogen in allergic inflammatory response.

View Article: PubMed Central - PubMed

Affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan; Department of Clinical Laboratory Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.

ABSTRACT
Estrogen influences the disease severity and sexual dimorphism in asthma, which is caused by complex mechanisms. Besides classical nuclear estrogen receptors (ERαβ), G-protein-coupled estrogen receptor (GPER) was recently established as an estrogen receptor on the cell membrane. Although GPER is associated with immunoregulatory functions of estrogen, the pathophysiological role of GPER in allergic inflammatory lung disease has not been examined. We investigated the effect of GPER-specific agonist G-1 in asthmatic mice. GPER expression in asthmatic lung was confirmed by immunofluorescent staining. OVA-sensitized BALB/c and C57BL/6 mice were treated with G-1 by daily subcutaneous injections during an airway challenge phase, followed by histological and biochemical examination. Strikingly, administration of G-1 attenuated airway hyperresponsiveness, accumulation of inflammatory cells, and levels of Th2 cytokines (IL-5 and IL-13) in BAL fluid. G-1 treatment also decreased serum levels of anti-OVA IgE antibodies. The frequency of splenic Foxp3+CD4+ regulatory T cells and IL-10-producing GPER+CD4+ T cells was significantly increased in G-1-treated mice. Additionally, splenocytes isolated from G-1-treated mice showed greater IL-10 production. G-1-induced amelioration of airway inflammation and IgE production were abolished in IL-10-deficient mice. Taken together, these results indicate that extended GPER activation negatively regulates the acute asthmatic condition by altering the IL-10-producing lymphocyte population. The current results have potential importance for understanding the mechanistic aspects of function of estrogen in allergic inflammatory response.

No MeSH data available.


Related in: MedlinePlus

Decreased AHR in G-1-treated asthmatic BALB/c mice.Development of AHR was measured by increased lung resistance (Rl, left panel) and decreased dynamic lung compliance (Cdyn, right panel) in response to methacholine. AHR was significantly decreased in G-1-treated mice compared to controls. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 6).
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pone.0123210.g002: Decreased AHR in G-1-treated asthmatic BALB/c mice.Development of AHR was measured by increased lung resistance (Rl, left panel) and decreased dynamic lung compliance (Cdyn, right panel) in response to methacholine. AHR was significantly decreased in G-1-treated mice compared to controls. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 6).

Mentions: Increased AHR induced by an immunologically non-specific stimulant such as methacholine is a fundamental feature of asthma. OVA-induced asthmatic mice develop AHR in response to increasing doses of inhaled methacholine. We examined the changes in airway resistance (reflecting AHR in large airways) and dynamic lung compliance (reflecting AHR in small airway) to assess whether G-1 administration influences AHR. As shown in Fig 2, in response to inhaled methacholine, asthmatic mice treated with phosphate buffered saline (PBS) had an increase in airway resistance and a decrease in lung compliance. In contrast, these responses to methacholine were significantly attenuated in G-1-treated asthmatic mice, indicating the suppression of AHR.


G-protein-coupled estrogen receptor agonist suppresses airway inflammation in a mouse model of asthma through IL-10.

Itoga M, Konno Y, Moritoki Y, Saito Y, Ito W, Tamaki M, Kobayashi Y, Kayaba H, Kikuchi Y, Chihara J, Takeda M, Ueki S, Hirokawa M - PLoS ONE (2015)

Decreased AHR in G-1-treated asthmatic BALB/c mice.Development of AHR was measured by increased lung resistance (Rl, left panel) and decreased dynamic lung compliance (Cdyn, right panel) in response to methacholine. AHR was significantly decreased in G-1-treated mice compared to controls. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 6).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380451&req=5

pone.0123210.g002: Decreased AHR in G-1-treated asthmatic BALB/c mice.Development of AHR was measured by increased lung resistance (Rl, left panel) and decreased dynamic lung compliance (Cdyn, right panel) in response to methacholine. AHR was significantly decreased in G-1-treated mice compared to controls. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 6).
Mentions: Increased AHR induced by an immunologically non-specific stimulant such as methacholine is a fundamental feature of asthma. OVA-induced asthmatic mice develop AHR in response to increasing doses of inhaled methacholine. We examined the changes in airway resistance (reflecting AHR in large airways) and dynamic lung compliance (reflecting AHR in small airway) to assess whether G-1 administration influences AHR. As shown in Fig 2, in response to inhaled methacholine, asthmatic mice treated with phosphate buffered saline (PBS) had an increase in airway resistance and a decrease in lung compliance. In contrast, these responses to methacholine were significantly attenuated in G-1-treated asthmatic mice, indicating the suppression of AHR.

Bottom Line: Although GPER is associated with immunoregulatory functions of estrogen, the pathophysiological role of GPER in allergic inflammatory lung disease has not been examined.G-1 treatment also decreased serum levels of anti-OVA IgE antibodies.The current results have potential importance for understanding the mechanistic aspects of function of estrogen in allergic inflammatory response.

View Article: PubMed Central - PubMed

Affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan; Department of Clinical Laboratory Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.

ABSTRACT
Estrogen influences the disease severity and sexual dimorphism in asthma, which is caused by complex mechanisms. Besides classical nuclear estrogen receptors (ERαβ), G-protein-coupled estrogen receptor (GPER) was recently established as an estrogen receptor on the cell membrane. Although GPER is associated with immunoregulatory functions of estrogen, the pathophysiological role of GPER in allergic inflammatory lung disease has not been examined. We investigated the effect of GPER-specific agonist G-1 in asthmatic mice. GPER expression in asthmatic lung was confirmed by immunofluorescent staining. OVA-sensitized BALB/c and C57BL/6 mice were treated with G-1 by daily subcutaneous injections during an airway challenge phase, followed by histological and biochemical examination. Strikingly, administration of G-1 attenuated airway hyperresponsiveness, accumulation of inflammatory cells, and levels of Th2 cytokines (IL-5 and IL-13) in BAL fluid. G-1 treatment also decreased serum levels of anti-OVA IgE antibodies. The frequency of splenic Foxp3+CD4+ regulatory T cells and IL-10-producing GPER+CD4+ T cells was significantly increased in G-1-treated mice. Additionally, splenocytes isolated from G-1-treated mice showed greater IL-10 production. G-1-induced amelioration of airway inflammation and IgE production were abolished in IL-10-deficient mice. Taken together, these results indicate that extended GPER activation negatively regulates the acute asthmatic condition by altering the IL-10-producing lymphocyte population. The current results have potential importance for understanding the mechanistic aspects of function of estrogen in allergic inflammatory response.

No MeSH data available.


Related in: MedlinePlus