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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

Inflammatory cell accumulation was significantly decreased in G-1-treated C57BL/6 mice compared to non-treated controls.A: H&E staining (original magnification: x40 and x400, upper panels) and PAS staining (x400, lower left panel) and MT staining (x400, lower right panel) of serial lung sections. B: Quantified data of inflammatory cell accumulation, histologically examined in H&E–stained lung tissue, as described in Materials and Methods. C: Inflammatory cell accumulation in BAL fluid. Values are expressed as the mean ± SEM. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 7).
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pone.0123210.g005: Inflammatory cell accumulation was significantly decreased in G-1-treated C57BL/6 mice compared to non-treated controls.A: H&E staining (original magnification: x40 and x400, upper panels) and PAS staining (x400, lower left panel) and MT staining (x400, lower right panel) of serial lung sections. B: Quantified data of inflammatory cell accumulation, histologically examined in H&E–stained lung tissue, as described in Materials and Methods. C: Inflammatory cell accumulation in BAL fluid. Values are expressed as the mean ± SEM. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 7).

Mentions: BALB/c mice are thought to be immunologically Th2 shifted and thus used in asthmatic models more frequently than C57BL/6 mice. To examine whether the G-1-induced anti-inflammatory effects are limited to the Th2-shifted strain, we performed the same experiment using C57BL/6 mice. In H&E-stained lung sections, inflammatory cells in the peribronchial areas were significantly decreased in G-1-treated C57BL/6 mice (Fig 5A and 5B). PAS-stained goblet cells in airway epithelium and MT-stained collagen were decreased in G-1-treated mice (Fig 5A), similar to those in G-1-treated BALB/c mice (Fig 3A). G-1 administration significantly reduced the number of total cells, eosinophils, and lymphocytes in BAL fluids of C57BL/6 mice (Fig 5C). Administration of G-1 significantly reduced the levels of IL-5 and IL-13 in BAL fluid and serum levels of total and OVA-specific IgE antibodies in C57BL/6 mice, as well (Fig 6A and 6B). These findings indicate that the inhibition of allergic airway inflammation by G-1 is not dependent on the strain of mouse.


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)

Inflammatory cell accumulation was significantly decreased in G-1-treated C57BL/6 mice compared to non-treated controls.A: H&E staining (original magnification: x40 and x400, upper panels) and PAS staining (x400, lower left panel) and MT staining (x400, lower right panel) of serial lung sections. B: Quantified data of inflammatory cell accumulation, histologically examined in H&E–stained lung tissue, as described in Materials and Methods. C: Inflammatory cell accumulation in BAL fluid. Values are expressed as the mean ± SEM. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 7).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123210.g005: Inflammatory cell accumulation was significantly decreased in G-1-treated C57BL/6 mice compared to non-treated controls.A: H&E staining (original magnification: x40 and x400, upper panels) and PAS staining (x400, lower left panel) and MT staining (x400, lower right panel) of serial lung sections. B: Quantified data of inflammatory cell accumulation, histologically examined in H&E–stained lung tissue, as described in Materials and Methods. C: Inflammatory cell accumulation in BAL fluid. Values are expressed as the mean ± SEM. * P<0.05, ** P<0.01, G-1-treated (n = 6) vs. non-treated mice (n = 7).
Mentions: BALB/c mice are thought to be immunologically Th2 shifted and thus used in asthmatic models more frequently than C57BL/6 mice. To examine whether the G-1-induced anti-inflammatory effects are limited to the Th2-shifted strain, we performed the same experiment using C57BL/6 mice. In H&E-stained lung sections, inflammatory cells in the peribronchial areas were significantly decreased in G-1-treated C57BL/6 mice (Fig 5A and 5B). PAS-stained goblet cells in airway epithelium and MT-stained collagen were decreased in G-1-treated mice (Fig 5A), similar to those in G-1-treated BALB/c mice (Fig 3A). G-1 administration significantly reduced the number of total cells, eosinophils, and lymphocytes in BAL fluids of C57BL/6 mice (Fig 5C). Administration of G-1 significantly reduced the levels of IL-5 and IL-13 in BAL fluid and serum levels of total and OVA-specific IgE antibodies in C57BL/6 mice, as well (Fig 6A and 6B). These findings indicate that the inhibition of allergic airway inflammation by G-1 is not dependent on the strain of mouse.

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