國家衛生研究院 NHRI:Item 3990099045/10037
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    题名: HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to T-cell-mediated type 2 diabetes
    作者: Chuang, HC;Tan, TH
    贡献者: Immunology Research Center
    摘要: Proinflammatory cytokines play important roles in insulin resistance. Here we report that T-cell-specific conditional HGK (MAP4K4) knockout (T-HGK cKO) mice developed systemic inflammation and insulin resistance, which was ameliorated by either IL-6 or IL-17 neutralization. HGK directly phosphorylated TRAF2 at Ser-35, leading to lysosomal degradation of TRAF2 and subsequent inhibition of IL-6 production. HGK kinase activity was decreased and TRAF2 protein levels were increased under TCR signaling, suggesting that HGK maintains a resting state of T cells. Thus, HGK knockout T cells constitutively displayed overexpression of TRAF2 and overproduction of IL-6. IL-6-overproducing HGK knockout T cells were attracted to adipose tissue by the CCL20-CCR6 axis; the accumulation of HGK knockout T cells in adipose tissue was blocked by CCR6 knockout. In adipose tissue, IL-6 secreted from HGK knockout T cells enhanced the levels of the adipokine leptin. The data derived from T-cell-specific leptin receptor/HGK double knockout mice or IL-6 KO/HGK cKO mice demonstrated that IL-6-overproducing HGK knockout T cells further differentiated into Th17 cells by a synergistic effect of leptin and IL-6. Adoptive transfer experiments further showed that these IL6/IL-17 double-positive T cells were pathogenic cells for insulin resistance. Clinical samples from type 2 diabetes (T2D) patients were used to study the clinical relevance. Notably, HGK levels fell and IL-6 levels increased in T cells from T2D patients. The clinical significance of HGK-deficient T cells will be presented in the meeting. Taken together, HGK plays important roles in the generation of adiposetissue Th17 cells and the pathogenesis of T-cell-mediated T2D.
    日期: 2016-08
    關聯: European Journal of Immunology. 2016 Aug;46(Suppl. 1):84-85.
    Link to: http://dx.doi.org/10.1002/eji.201670200
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0014-2980&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000383610400170
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