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http://ir.nhri.org.tw/handle/3990099045/12029
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| Title: | AhR-ROR-gammat complex is a therapeutic target for MAP4K3/GLK(high)IL-17A(high) subpopulation of systemic lupus erythematosus |
| Other Titles: | AhR-ROR-γt complex is a therapeutic target for MAP4K3/GLKhighIL-17Ahigh subpopulation of systemic lupus erythematosus |
| Authors: | Chuang, HC;Chen, YM;Chen, MH;Hung, WT;Yang, HY;Tseng, YH;Tan, TH |
| Contributors: | Immunology Research Center |
| Abstract: | 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. |
| Date: | 2019-10 |
| Relation: | 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 |
| Appears in Collections: | [莊懷佳] 期刊論文
[譚澤華] 期刊論文
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| PUB31318609.pdf | | 1979Kb | Adobe PDF | 285 | View/Open |
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