Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells
Glucocorticoid therapy of antigen-induced arthritis depends on the dimerized glucocorticoid receptor in T cells
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DOI：
10.1073/pnas.1105857108
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发表时间：
2011-11-29
影响因子：
11.1
通讯作者：
Tuckermann, Jan P.
中科院分区：
文献类型：
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作者：
Baschant, Ulrike;Frappart, Lucien;Tuckermann, Jan P.
尽管有一些副作用，糖皮质激素（GC）已被广泛用于治疗类风湿性关节炎的基础上，其副作用60年。然而，在类固醇治疗中，GC靶向的细胞及其通过糖皮质激素受体（GR）发挥作用的转录机制仍不清楚。使用细胞类型特异性GR缺陷小鼠进行抗原诱导的关节炎（AIA）作为人类类风湿性关节炎的模型，我们表明，GC对T细胞的作用，而不是骨髓细胞是至关重要的AIA的治疗干预。此外，表达DNA结合缺陷型GR（GR（dim））的小鼠对GC处理的抗性揭示了GR的二聚化对于GC效应是不可或缺的。在这些小鼠中，GC诱导的T（H）1和T（H）17细胞衍生的促炎性细胞因子的抑制受损。我们发现IL-17 A（-/-）小鼠对GC治疗有抗性，而IFN-γ（-/-）小鼠与WT小鼠一样有效地应答，这意味着产生IL-17的T细胞而不是产生IFN-γ的T细胞是有效GC治疗的最重要靶点。本研究确定的关键细胞类型和GR的作用模式，在AIA的类固醇治疗显着推进我们的理解类固醇治疗，并应导致更高的效率和更少的副作用的治疗。
Despite several side effects, glucocorticoids (GCs) have been widely used for 60 y to treat rheumatoid arthritis on the basis of their antiinflammatory effects. However, the cells targeted by GCs and the transcriptional mechanisms underlying their actions through the glucocorticoid receptor (GR) in steroid therapy remain poorly defined. Using cell type-specific GR-deficient mice subjected to antigen-induced arthritis (AIA) as a model of human rheumatoid arthritis, we show that GC action on T cells but not myeloid cells is critical for therapeutic intervention in AIA. Furthermore, the resistance of mice expressing a DNA binding-defective GR (GR(dim)) to GC treatment reveals that dimerization of the GR is indispensable for the antiinflammatory effects. In these mice, the GC-induced suppression of T(H)1 and T(H)17 cell-derived proinflammatory cytokines is impaired. Our finding that IL-17A(-/-) mice are resistant to GC therapy, whereas IFN-gamma(-/-) mice respond as efficiently as WT mice implies that IL-17-producing T cells and not IFN-gamma-producing T cells are the most important targets for an efficient GC therapy. The present study's identification of the critical cell type and the mode of GR action in steroid therapy of AIA significantly advances our understanding of steroid therapy and should lead to therapies with greater efficiency and fewer side effects.