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

• Published in: PloS one 2015-03, Vol.10 (3), p.e0123210-e0123210
• Main Authors: Itoga, Masamichi, Konno, Yasunori, Moritoki, Yuki, Saito, Yukiko, Ito, Wataru, Tamaki, Mami, Kobayashi, Yoshiki, Kayaba, Hiroyuki, Kikuchi, Yuta, Chihara, Junichi, Takeda, Masahide, Ueki, Shigeharu, Hirokawa, Makoto
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antigens; Asthma; Asthma - complications; Asthma - prevention & control; B cells; Binding sites; Bronchitis - prevention & control; CD4 antigen; Cell activation; Chemokines - metabolism; Cloning; Cytokines; Cytokines - metabolism; Disease Models, Animal; Estrogen receptors; Estrogens; Female; Foxp3 protein; G protein-coupled receptors; Gene expression; House mouse; Hypersensitivity; Immunoglobulin E; Immunoregulation; Inflammation; Inflammatory response; Interleukin 10; Interleukin 13; Interleukin 5; Interleukin-10 - genetics; Interleukin-10 - physiology; Internal medicine; Laboratories; Lung - metabolism; Lung diseases; Lymphocytes; Lymphocytes T; Medicine; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Phenols (Class of compounds); Proteins; Receptors; Receptors, Estrogen - drug effects; Receptors, Estrogen - metabolism; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Respiratory tract; Respiratory tract diseases; Serum levels; Sexual dimorphism; Spleen; Splenocytes; University graduates; Womens health
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0123210

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.