title: STAT6 deficiency ameliorates Graves' disease severity by suppressing thyroid epithelial cell hyperplasia.
abstract: Signal transducer and activator of transcription 6 (STAT6) is involved in epithelial cell growth. However, little is known regarding the STAT6 phosphorylation status in Graves' disease (GD) and its role in thyroid epithelial cells (TECs). In this study, we found that STAT6 phosphorylation (p-STAT6) was significantly increased in TECs from both GD patients and experimental autoimmune Graves' disease mice and that STAT6 deficiency ameliorated GD symptoms. Autocrine IL-4 signalling in TECs activated the phosphorylation of STAT6 via IL-4 R engagement, and the downstream targets of STAT6 were Bcl-xL and cyclin D1. Thus, the IL-4-STAT6-Bcl-xL/cyclin D1 pathway is crucial for TEC hyperplasia, which aggravates GD. More importantly, in vitro and in vivo experiments demonstrated that STAT6 phosphorylation inhibited by AS1517499 decreased TEC hyperplasia, thereby reducing serum T3 and T4 and ameliorating GD. Thus, our study reveals that in addition to the traditional pathogenesis of GD, in which autoantibody TRAb stimulates thyroid-stimulating hormone receptors and consequently produces T3, T4, TRAb could also trigger TECs producing IL-4, and IL-4 then acts in an autocrine manner to activate p-STAT6 signalling and stimulate unrestricted cell growth, thus aggravating GD. These findings suggest that STAT6 inhibitors could be potent therapeutics for treating GD.
authors.affiliation: Department of Immunology and Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Biotherapy Research Center of Fudan University, Shanghai, 200032, China.|Scientific Research Center, Xinhua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, PR China.
authors.forename: Xuechao
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
authors.forename: Bingbing
authors.initials: B
authors.lastname: Zha
authors.affiliation: Department of Immunology and Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Biotherapy Research Center of Fudan University, Shanghai, 200032, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Immunology and Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Biotherapy Research Center of Fudan University, Shanghai, 200032, China.
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Immunology and Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Biotherapy Research Center of Fudan University, Shanghai, 200032, China.
authors.forename: Enyu
authors.initials: E
authors.lastname: Huang
authors.affiliation: Department of Immunology and Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Biotherapy Research Center of Fudan University, Shanghai, 200032, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Qian
authors.affiliation: Department of Immunology and Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Biotherapy Research Center of Fudan University, Shanghai, 200032, China.
authors.forename: Jiajing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Immunology and Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Biotherapy Research Center of Fudan University, Shanghai, 200032, China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Immunology and Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Biotherapy Research Center of Fudan University, Shanghai, 200032, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Immunology and Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Biotherapy Research Center of Fudan University, Shanghai, 200032, China.
authors.forename: Luman
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Immunology and Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences, Biotherapy Research Center of Fudan University, Shanghai, 200032, China.
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chu
mesh_terms: D000818:Animals; D019938:Cyclin D1 / Q000378:metabolism; D006111:Graves Disease / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia; D015847:Interleukin-4 / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000172:deficiency* / Q000378:metabolism; D012720:Severity of Illness Index; D000072637:Thyroid Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C544923:4-(benzylamino)-2-((2-(3-chloro-4-hydroxyphenyl)ethyl)amino)pyrimidine-5-carboxamide; D011743:Pyrimidines; D018123:Receptors, Interleukin; D050800:STAT6 Transcription Factor; D051020:bcl-X Protein; D019938:Cyclin D1; D015847:Interleukin-4