Identification of a lysosomal pathway that modulates glucocorticoid signaling and the inflammatory response.
Identification of a lysosomal pathway that modulates glucocorticoid signaling and the inflammatory response.
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DOI：
10.1126/scisignal.2001450
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发表时间：
2011-07-05
影响因子：
7.3
通讯作者：
Xu HE
中科院分区：
文献类型：
--
作者：
He Y;Xu Y;Zhang C;Gao X;Dykema KJ;Martin KR;Ke J;Hudson EA;Khoo SK;Resau JH;Alberts AS;MacKeigan JP;Furge KA;Xu HE
抗疟药氯喹已被用作治疗系统性红斑狼疮和类风湿性关节炎的抗炎剂。我们报告氯喹促进促炎细胞因子的糖皮质激素受体（GR）的反式阻遏。在小鼠胶原诱导的关节炎模型中，氯喹增强了糖皮质激素治疗的疗效。通过抑制溶酶体功能，氯喹协同激活糖皮质激素信号传导。通过巴弗洛霉素A1（空泡腺苷三磷酸酶的抑制剂）或转录因子EB（TFEB，溶酶体生物发生的主激活剂）的敲低来抑制溶酶体，模仿氯喹的作用。GR以及雄激素受体和雌激素受体的丰度与溶酶体生物合成的变化相关。因此，我们发现糖皮质激素信号传导受溶酶体调节，这为用糖皮质激素和溶酶体抑制剂的组合治疗炎症和自身免疫性疾病提供了机制基础。
The antimalaria drug chloroquine has been used as an anti-inflammatory agent for treating systemic lupus erythematosus and rheumatoid arthritis. We report that chloroquine promoted the transrepression of proinflammatory cytokines by the glucocorticoid receptor (GR). In a mouse collagen-induced arthritis model, chloroquine enhanced the therapeutic effects of glucocorticoid treatment. By inhibiting lysosome function, chloroquine synergistically activated glucocorticoid signaling. Lysosomal inhibition by either bafilomycin A1 (an inhibitor of the vacuolar adenosine triphosphatase) or knockdown of transcription factor EB (TFEB, a master activator of lysosomal biogenesis) mimicked the effects of chloroquine. The abundance of the GR, as well as that of the androgen receptor and estrogen receptor, correlated with changes in lysosomal biogenesis. Thus, we showed that glucocorticoid signaling is regulated by lysosomes, which provides a mechanistic basis for treating inflammation and autoimmune diseases with a combination of glucocorticoids and lysosomal inhibitors.
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影响因子：
82.9
作者：
Chen, CD;Welsbie, DS;Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
64.8
作者：
DORN, A;STOFFEL, R;RIDLEY, RG
通讯作者：
RIDLEY, RG
影响因子：
64.5
作者：
CIECHANOVER, A;FINLEY, D;VARSHAVSKY, A
通讯作者：
VARSHAVSKY, A
影响因子：
--
作者：
Cho, SY;Kagan, BL;Simons, SS
通讯作者：
Simons, SS