Blunting Autoantigen-induced FOXO3a Protein Phosphorylation and Degradation Is a Novel Pathway of Glucocorticoids for the Treatment of Systemic Lupus Erythematosus
Blunting Autoantigen-induced FOXO3a Protein Phosphorylation and Degradation Is a Novel Pathway of Glucocorticoids for the Treatment of Systemic Lupus Erythematosus
复制标题
减弱自身抗原诱导的 FOXO3a 蛋白磷酸化和降解是糖皮质激素治疗系统性红斑狼疮的新途径
DOI：
10.1074/jbc.m116.728840
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发表时间：
2016-09-16
影响因子：
4.8
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
--
作者：
Lu, Mudan;Xu, Wei;Xiong, Sidong
系统性红斑狼疮（SLE）是一种累及多器官的慢性炎症性自身免疫性疾病。糖皮质激素（GCs）是一种强效抗炎药物，仍然是SLE治疗的基石；然而，长期治疗的副作用和耐药性影响了其临床疗效。为了提高糖皮质激素在SLE治疗中的疗效，进一步阐明糖皮质激素发挥抗炎作用的分子机制非常重要。在本研究中，FOXO3a被鉴定为在SLE过程中下调的分子。有趣的是，发现糖皮质激素治疗可恢复SLE小鼠和SLE患者中FOXO3a的表达。功能获得和功能缺失研究表明，FOXO3a通过抑制炎症反应在糖皮质激素治疗SLE中起关键作用。进一步的研究表明，糖皮质激素对FOXO3a的上调依赖于对PI3K/AKT介导的FOXO3a磷酸化的抑制以及FOXO3a在细胞核内的滞留。最后，我们的数据显示FOXO3a对糖皮质激素介导的NF - κB活性抑制至关重要，这可能涉及其与NF - κB p65蛋白的相互作用。总之，这些数据表明FOXO3a通过抑制促炎反应在糖皮质激素治疗SLE中起重要作用，靶向FOXO3a可能为SLE提供一种新的治疗策略。
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease affecting multiple organs. Glucocorticoids (GCs), the potent anti-inflammatory drugs, remain as a cornerstone in the treatment for SLE; nevertheless, their clinical efficacy is compromised by the side effects of long term treatment and resistance. To improve the therapeutic efficacy of GCs in SLE, it is important to further decipher the molecular mechanisms of how GCs exert their anti-inflammatory effects. In this investigation, FOXO3a was identified as a molecule that was down-regulated in the course of SLE. Of interest, GC treatment was found to rescue FOXO3a expression both in SLE mice and in SLE patients. Gain- and loss-of-function studies demonstrated that FOXO3a played a crucial role in GC treatment of SLE via inhibiting inflammatory responses. Further studies showed that the up-regulation of FOXO3a by GCs relied on the suppression of pI3K/AKT-mediated FOXO3a phosphorylation and the arrest of FOXO3a in the nucleus. Finally, our data revealed that FOXO3a was critical for GC-mediated inhibition of NF-B activity, which might involve its interaction with NF-B p65 protein. Collectively, these data indicated that FOXO3a played an important role in GC treatment of SLE by suppressing pro-inflammatory response, and targeting FOXO3a might provide a novel therapeutic strategy against SLE.