Upregulated IL-1 Receptor-associated Kinase 1 (IRAK1) in Systemic Lupus Erythematosus: IRAK1 Inhibition Represses Th17 Differentiation with Therapeutic Potential
Upregulated IL-1 Receptor-associated Kinase 1 (IRAK1) in Systemic Lupus Erythematosus: IRAK1 Inhibition Represses Th17 Differentiation with Therapeutic Potential
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系统性红斑狼疮中 IL-1 受体相关激酶 1 (IRAK1) 上调：IRAK1 抑制可抑制 Th17 分化并具有治疗潜力
DOI：
10.1080/08820139.2018.1458105
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发表时间：
2018-04
影响因子：
2.8
通讯作者：
郝飞
中科院分区：
文献类型：
--
作者：
周舟;田志强;张梦洁;张玉勋;倪兵;郝飞
系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病。全基因组分析显示，白细胞介素-1受体相关激酶1（IRAK 1）与SLE易感性相关。我们先前的研究探讨了IRAK 1在狼疮小鼠模型中核因子-κB（NF-κB）相关通路中的作用。在这项研究中，我们的目的是进一步探讨IRAK 1的病因作用。采用定量逆转录-聚合酶链反应（RT-PCR）和免疫印迹法（Western blotting）分别检测狼疮患者和健康对照者CD 4 + T细胞中IRAK 1的基因表达和磷酸化水平。采用流式细胞术和酶联免疫吸附试验分别检测外周血Th 17细胞百分比和血浆IL-17 A水平。使用IRAK 1抑制剂和小干扰RNA评估IRAK 1抑制对Th 17发育的影响。我们发现，与对照组相比，SLE患者CD 4 + T细胞中的IRAK 1转录水平显著上调，且与疾病活动呈正相关。体外实验显示，在IL-1β刺激后，狼疮CD 4 + T细胞在苏氨酸-209处具有比对照细胞更显著的IRAK 1磷酸化。此外，IRAK 1表达与患者中的Th 17/IL-17 A正相关。当幼稚CD 4 + T细胞向Th 17亚群极化时，IRAK 1抑制显著抑制IL-17 A的产生和Th 17标志物的基因表达，即视黄酸受体相关孤儿受体c、IL-23受体和IL-17 A。总之，IRAK 1在SLE患者的CD 4 + T细胞中过表达和过度活化。IRAK 1抑制减弱了人SLE背景下的Th 17分化，提示了治疗机会。
ABSTRACT Systemic lupus erythematosus (SLE) is a typical autoimmune disease. Genome-wide analyses have revealed that interleukin-1 receptor-associated kinase 1 (IRAK1) is associated with susceptibility to SLE. Our previous study investigated the role of IRAK1 in nuclear factor-κB (NF-κB)-related pathways in a mouse model of lupus. In this study, we aimed to further explore the etiological role of IRAK1. The gene expression and phosphorylation of IRAK1 in CD4+ T cells from lupus patients and healthy controls were examined by quantitative reverse transcription-polymerase chain reaction and western blotting, respectively. The percentage of circulating Th17 cells and plasma IL-17A levels were evaluated by flow cytometry and enzyme-linked immunosorbent assay, respectively. The influence of IRAK1 suppression on Th17 development was assessed using an IRAK1 inhibitor and small interfering RNA. We found that IRAK1 transcript levels in CD4+ T cells were significantly upregulated in SLE patients in comparison to controls and were positively correlated with disease activity. In vitro experiments showed that lupus CD4+ T cells had more pronounced IRAK1 phosphorylation at threonine-209 upon IL-1β stimulation than did control cells. Moreover, IRAK1 expression was positively associated with Th17/IL-17A in patients. When naïve CD4+ T cells were polarized toward the Th17 subset, IRAK1 inhibition significantly repressed IL-17A production and the gene expression of Th17 markers, namely, retinoic acid receptor-related orphan receptor c, IL-23 receptor and IL-17A. In summary, IRAK1 is overexpressed and hyperactivated in CD4+ T cells from SLE patients. IRAK1 inhibition attenuates Th17 differentiation in the context of human SLE, suggesting a therapeutic opportunity.
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影响因子：
7.3
作者：
Sha Y;Markovic-Plese S
通讯作者：
Markovic-Plese S
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影响因子：
32.4
作者：
Garlanda C;Dinarello CA;Mantovani A
通讯作者：
Mantovani A
Interleukin-1 受体相关激酶在 Vogt-Koyanagi-Harada 病中的作用
影响因子：
3.7
作者：
Sun M;Yang P;Du L;Yang Y;Ye J
通讯作者：
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影响因子：
1.9
作者：
W. Raymond;G. Ostli-Eilertsen;S. Griffiths;J. Nossent
通讯作者：
W. Raymond;G. Ostli-Eilertsen;S. Griffiths;J. Nossent
影响因子：
6.7
作者：
Zhai, Yu;Xu, Ke;Ye, Dong-Qing
通讯作者：
Ye, Dong-Qing