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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

Th2 cytokines and IgE were decreased in G-1-treated BALB/c mice compared to non-treated controls.A, B: The levels of eotaxin, IL-4, IL-5, IL-13, and IFN-γ in BAL fluid and total and OVA-specific IgE antibodies in serum of mice were measured using ELISA. The results are expressed as the mean ± SEM. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 6).
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pone.0123210.g004: Th2 cytokines and IgE were decreased in G-1-treated BALB/c mice compared to non-treated controls.A, B: The levels of eotaxin, IL-4, IL-5, IL-13, and IFN-γ in BAL fluid and total and OVA-specific IgE antibodies in serum of mice were measured using ELISA. The results are expressed as the mean ± SEM. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 6).

Mentions: Since G-1 attenuated OVA-induced lung inflammation, we measured levels of Th1 and Th2 cytokines (IL-4, 5, and 13 and INF-γ) and an eosinophil-driving chemokine eotaxin (CCL11) in BAL fluid using ELISA. Administration of G-1 significantly reduced the levels of IL-5 and IL-13 in BAL fluid compared with non-treated mice (Fig 4A). We also assessed the serum levels of total and OVA-specific IgE. As shown in Fig 4B, OVA-specific IgE was significantly reduced in G-1-treated asthmatic mice. These data suggest that G-1 administration attenuates Th2 cytokines in lung and antigen-specific B cell response in this asthmatic model of mice.


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)

Th2 cytokines and IgE were decreased in G-1-treated BALB/c mice compared to non-treated controls.A, B: The levels of eotaxin, IL-4, IL-5, IL-13, and IFN-γ in BAL fluid and total and OVA-specific IgE antibodies in serum of mice were measured using ELISA. The results are expressed as the mean ± SEM. * 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.g004: Th2 cytokines and IgE were decreased in G-1-treated BALB/c mice compared to non-treated controls.A, B: The levels of eotaxin, IL-4, IL-5, IL-13, and IFN-γ in BAL fluid and total and OVA-specific IgE antibodies in serum of mice were measured using ELISA. The results are expressed as the mean ± SEM. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 6).
Mentions: Since G-1 attenuated OVA-induced lung inflammation, we measured levels of Th1 and Th2 cytokines (IL-4, 5, and 13 and INF-γ) and an eosinophil-driving chemokine eotaxin (CCL11) in BAL fluid using ELISA. Administration of G-1 significantly reduced the levels of IL-5 and IL-13 in BAL fluid compared with non-treated mice (Fig 4A). We also assessed the serum levels of total and OVA-specific IgE. As shown in Fig 4B, OVA-specific IgE was significantly reduced in G-1-treated asthmatic mice. These data suggest that G-1 administration attenuates Th2 cytokines in lung and antigen-specific B cell response in this asthmatic model of mice.

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