title: G-protein-coupled estrogen receptor agonist suppresses airway inflammation in a mouse model of asthma through IL-10.
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.
authors.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.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Itoga
authors.affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan; Division of Dentistry and Oral Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Konno
authors.affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Moritoki
authors.affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan; Nagareyama Tobu Clinic, 909-1 Nazukari, Nagareyama City, Chiba, 270-0145, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ito
authors.affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Tamaki
authors.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 Otolaryngology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata City, Osaka, 573-1010, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kobayashi
authors.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.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kayaba
authors.affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Kikuchi
authors.affiliation: Soseikai General Hospital, 101 Shimotoba Hiroosacho, Fushimi-ku, Kyoto City, Kyoto, 612-8473, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Chihara
authors.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 Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Masahide
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Shigeharu
authors.initials: S
authors.lastname: Ueki
authors.affiliation: Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Hirokawa
mesh_terms: D000818:Animals; D001249:Asthma / Q000150:complications* / Q000517:prevention & control; D001991:Bronchitis / Q000517:prevention & control*; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016753:Interleukin-10 / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011960:Receptors, Estrogen / Q000187:drug effects* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D016753:Interleukin-10
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