國家衛生研究院 NHRI:Item 3990099045/12029
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    题名: AhR-ROR-gammat complex is a therapeutic target for MAP4K3/GLK(high)IL-17A(high) subpopulation of systemic lupus erythematosus
    其它题名: AhR-ROR-γt complex is a therapeutic target for MAP4K3/GLKhighIL-17Ahigh subpopulation of systemic lupus erythematosus
    作者: Chuang, HC;Chen, YM;Chen, MH;Hung, WT;Yang, HY;Tseng, YH;Tan, TH
    贡献者: Immunology Research Center
    摘要: The cytokine IL-17A plays critical roles in the pathogenesis of autoimmune diseases. The frequencies of MAP kinase kinase kinase kinase 3 [also named germinal center kinase-like kinase (GLK)]-overexpressing T cells are correlated with disease severity of systemic lupus erythematosus (SLE). T-cell-specific GLK-transgenic mice develop spontaneous autoimmune responses through IL-17A. GLK signaling selectively stimulates IL-17A production in murine T cells through inducing aryl hydrocarbon receptor (AhR)-retinoic acid receptor-related orphan nuclear receptor-gammat (ROR-gammat) complex formation. Here, we investigated whether GLK-induced AhR-ROR-gammat complex in T cells is a therapeutic target for human SLE. The population of GLK(+)IL-17A(+) T cells was enhanced in the peripheral blood from patients with SLE compared with that of healthy controls using flow cytometry. The receiver operating characteristic curve analysis showed that increased GLK(+)IL-17A(+) T-cell population in peripheral blood reflected an active stage of SLE. In addition, peripheral blood T cells from patients with SLE displayed induction of ROR-gammat phosphorylation and the AhR-ROR-gammat (and AhR-phosphorylated ROR-gammat) complex. Moreover, we identified a small-molecule inhibitor, verteporfin (C1), that inhibited GLK kinase activity and AhR-ROR-gammat interaction. The small-molecule inhibitor verteporfin suppressed the disease severity in autoimmune mouse models and IL-17A production in T cells from patients with SLE. Collectively, the GLK-induced AhR-ROR-gammat (and AhR-phosphorylated ROR-gammat) complex is a therapeutic target for the GLK(high)IL-17A(high) subpopulation of human patients with SLE.-Chuang, H.-C., Chen, Y.-M., Chen, M.-H., Hung, W.-T., Yang, H.-Y., Tseng, Y.-H., Tan, T.-H. AhR-ROR-gammat complex is a therapeutic target for MAP4K3/GLK(high)IL-17A(high) subpopulation of systemic lupus erythematosus.
    日期: 2019-10
    關聯: FASEB Journal. 2019 Oct;3(10):11469-11480.
    Link to: http://dx.doi.org/10.1096/fj.201900105RR
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0892-6638&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000489166300072
    Cited Times(Scopus): https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85072717996
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