Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells.
Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells.
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DOI：
10.1186/s13075-015-0588-3
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发表时间：
2015-03-22
影响因子：
4.9
通讯作者：
Gesualdo L
中科院分区：
文献类型：
--
作者：
Castellano G;Cafiero C;Divella C;Sallustio F;Gigante M;Pontrelli P;De Palma G;Rossini M;Grandaliano G;Gesualdo L
I 型干扰素对于系统性红斑狼疮自身免疫反应的激活至关重要。然而，干扰素-α 在狼疮性肾炎患者中的致病作用仍不确定。我们研究的目的是调查狼疮性肾炎中特定干扰素特征的存在以及干扰素-α在肾脏水平的影响。我们对 MXA 蛋白进行了免疫组织化学分析，并进行了原位杂交，以检测人狼疮性肾炎中的干扰素 α 特征和产生。通过微阵列研究，我们分析了用干扰素-α刺激的肾小管上皮细胞的基因表达谱。我们通过实时聚合酶链反应、肾小管上皮细胞的流式细胞术以及肾活检的免疫组织化学分析和共聚焦显微镜验证了微阵列结果。 I 型干扰素特征通过肾小管上皮细胞中的 MXA 特异性染色来表征；此外，原位杂交显示肾小管上皮细胞是干扰素-α的主要产生者，表明其具有潜在的自分泌作用。全基因组表达谱显示干扰素-α 诱导与先天免疫、蛋白质泛素化和转换为免疫蛋白酶体相关的基因上调。根据体外数据，IV 类狼疮性肾炎显示肾小管上皮细胞中与 I 型干扰素特征相关的免疫蛋白酶体亚基 LMP7 上调。我们的数据表明，I 型干扰素可能在狼疮性肾炎中具有致病作用，其特征是干扰素-α 对肾小管上皮细胞的自分泌作用。因此，我们假设 I 型干扰素的抑制可能是预防狼疮性肾炎患者肾小管间质损伤的治疗靶点。本文的在线版本 (doi:10.1186/s13075-015-0588-3) 包含补充材料，可供授权用户使用。
Type I interferons are pivotal in the activation of autoimmune response in systemic lupus erythematous. However, the pathogenic role of interferon-alpha in patients affected by lupus nephritis remains uncertain. The aim of our study was to investigate the presence of a specific interferon signature in lupus nephritis and the effects of interferon-alpha at renal level. We performed immunohistochemical analysis for MXA-protein and in situ hybridization to detect interferon-alpha signature and production in human lupus nephritis. Through microarray studies, we analyzed the gene expression profile of renal tubular epithelial cells, stimulated with interferon-alpha. We validated microarray results through real-time polymerase chain reaction, flow cytometry on renal tubular epithelial cells, and through immunohistochemical analysis and confocal microscopy on renal biopsies. Type I interferons signature was characterized by MXA-specific staining in renal tubular epithelial cells; in addition, in situ hybridization showed that renal tubular epithelial cells were the major producers of interferon-alpha, indicating a potential autocrine effect. Whole-genome expression profile showed interferon-alpha induced up-regulation of genes involved in innate immunity, protein ubiquitination and switching to immunoproteasome. In accordance with the in vitro data, class IV lupus nephritis showed up-regulation of the immunoproteasome subunit LMP7 in tubular epithelial cells associated with type I interferon signature. Our data indicate that type I interferons might have a pathogenic role in lupus nephritis characterized by an autocrine effect of interferon-alpha on renal tubular epithelial cells. Therefore we hypothesize that inhibition of type I interferons might represent a therapeutic target to prevent tubulo-interstitial damage in patients with lupus nephritis. The online version of this article (doi:10.1186/s13075-015-0588-3) contains supplementary material, which is available to authorized users.
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