Distinct regulation of murine lupus susceptibility genes by the IRF5/Blimp-1 axis.
Distinct regulation of murine lupus susceptibility genes by the IRF5/Blimp-1 axis.
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DOI：
10.4049/jimmunol.1102311
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发表时间：
2012-01-01
期刊：
影响因子：
--
通讯作者：
Choubey D
中科院分区：
文献类型：
--
作者：
Panchanathan R;Liu H;Liu H;Fang CM;Erickson LD;Pitha PM;Choubey D
全基因组关联研究已经确定了人类基因组中的狼疮易感基因，如IRF 5和PRDM 1（编码IRF 5和Blimp-1）。因此，鼠Irf 5和Prdm 1基因已被证明在狼疮易感性中起作用。然而，目前还不清楚IRF 5和Blimp-1（IRF 5的转录靶点）如何影响狼疮易感性。鉴于小鼠狼疮易感性基因座Nba 2包括干扰素调节基因Ifi 202（编码p202蛋白）、Aim 2（编码Aim 2蛋白）和Fcgr 2b（编码FcγRIIB受体），我们研究了IRF 5-Blimp-1轴是否可以调节这些基因的表达。我们发现，在小鼠中的Irf 5-缺陷减少了Blimp-1的表达，并减少了Ifi 202的表达。然而，该缺陷增加了Aim 2和Fcgr 2b的表达。相应地，细胞中IRF 5表达的增加增加了Blimp-1和p202蛋白的水平。此外，Blimp-1表达增加Ifi 202的表达，而其减少Aim 2的表达。有趣的是，雌性小鼠中的Aim 2缺陷增加了IRF 5的表达。类似地，Fcgr 2b缺陷小鼠表达增加的IRF 5水平。此外，在狼疮易感的B6.Nba2、NZB和B6.Sle123雌性小鼠中IRF 5和Blimp-1的表达增加（与年龄匹配的C57 BL/6雌性小鼠相比）与p202蛋白水平增加相关。总之，我们的观察结果表明，IRF 5-Blimp-1轴差异调节Nba 2狼疮易感基因的表达，并表明IRF 5-Blimp-1-p202轴在小鼠狼疮易感性中的重要作用。
Genome-wide association studies have identified lupus susceptibility genes such as IRF5 and PRDM1 (encoding for the IRF5 and Blimp-1) in the human genome. Accordingly, the murine Irf5 and Prdm1 genes have been shown to play a role in lupus susceptibility. However, it remains unclear how IRF5 and Blimp-1 (a transcriptional target of IRF5) contribute to lupus susceptibility. Given that the murine lupus susceptibility locus Nba2 includes the interferon-regulated genes Ifi202 (encoding for the p202 protein), Aim2 (encoding for the Aim2 protein), and Fcgr2b (encoding for the FcγRIIB receptor), we investigated whether the IRF5-Blimp-1 axis could regulate the expression of these genes. We found that an Irf5-deficiency in mice decreased the expression of Blimp-1 and reduced the expression of the Ifi202. However, the deficiency increased the expression of Aim2 and Fcgr2b. Correspondingly, increased expression of IRF5 in cells increased levels of Blimp-1 and p202 protein. Moreover, Blimp-1 expression increased the expression of Ifi202, whereas it reduced the expression of Aim2. Interestingly, an Aim2-deficiency in female mice increased the expression of IRF5. Similarly, the Fcgr2b-deficient mice expressed increased levels of IRF5. Moreover, increased expression of IRF5 and Blimp-1 in lupus-prone B6.Nba2, NZB, and B6.Sle123 female mice (as compared to age-matched C57BL/6 female mice) was associated with increased levels of the p202 protein. Together, our observations demonstrate that the IRF5-Blimp-1 axis differentially regulates the expression of Nba2 lupus susceptibility genes, and suggest an important role for the IRF5-Blimp-1-p202 axis in murine lupus susceptibility.
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发表时间：
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DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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