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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

IL-10 deprivation abolished G-1-induced improvement of inflammatory cell accumulation in the lung.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 for G-1-treated mice (n = 6) and non-treated controls (n = 7).
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pone.0123210.g008: IL-10 deprivation abolished G-1-induced improvement of inflammatory cell accumulation in the lung.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 for G-1-treated mice (n = 6) and non-treated controls (n = 7).

Mentions: Since IL-10 production was upregulated in splenocytes from G-1-treated mice, we examined G-1-treated lung inflammation in IL-10 KO mice with a C57BL/6 background. Histopathological examination demonstrated no significant differences in inflammatory cell accumulation, goblet cell hyperplasia, and lung fibrosis between G-1-treated and non-treated IL-10 KO mice (Fig 8A and 8B). In addition, the numbers and types of inflammatory cells in the airways did not differ regardless of G-1 treatment (Fig 8C).


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)

IL-10 deprivation abolished G-1-induced improvement of inflammatory cell accumulation in the lung.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 for G-1-treated mice (n = 6) and non-treated controls (n = 7).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123210.g008: IL-10 deprivation abolished G-1-induced improvement of inflammatory cell accumulation in the lung.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 for G-1-treated mice (n = 6) and non-treated controls (n = 7).
Mentions: Since IL-10 production was upregulated in splenocytes from G-1-treated mice, we examined G-1-treated lung inflammation in IL-10 KO mice with a C57BL/6 background. Histopathological examination demonstrated no significant differences in inflammatory cell accumulation, goblet cell hyperplasia, and lung fibrosis between G-1-treated and non-treated IL-10 KO mice (Fig 8A and 8B). In addition, the numbers and types of inflammatory cells in the airways did not differ regardless of G-1 treatment (Fig 8C).

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