狼疮性肾炎中α干扰素的局部合成与I型干扰素特征及肾小管上皮细胞中LMP7的诱导有关。
Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells.
作者信息
Castellano Giuseppe, Cafiero Cesira, Divella Chiara, Sallustio Fabio, Gigante Margherita, Pontrelli Paola, De Palma Giuseppe, Rossini Michele, Grandaliano Giuseppe, Gesualdo Loreto
机构信息
Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
C.A.R.S.O. Consortium, Valenzano, Bari, Italy.
出版信息
Arthritis Res Ther. 2015 Mar 22;17(1):72. doi: 10.1186/s13075-015-0588-3.
INTRODUCTION
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.
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
引言
I型干扰素在系统性红斑狼疮自身免疫反应的激活中起关键作用。然而，α干扰素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情况以及α干扰素在肾脏水平的作用。
方法
我们对MXA蛋白进行免疫组化分析，并进行原位杂交以检测人类狼疮性肾炎中的α干扰素特征和产生情况。通过微阵列研究，我们分析了用α干扰素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化分析和共聚焦显微镜检查来验证微阵列结果。
结果
I型干扰素特征表现为肾小管上皮细胞中MXA特异性染色；此外，原位杂交显示肾小管上皮细胞是α干扰素的主要产生者，表明存在潜在的自分泌效应。全基因组表达谱显示α干扰素诱导了参与固有免疫、蛋白质泛素化和向免疫蛋白酶体转换的基因上调。与体外数据一致，IV型狼疮性肾炎显示与I型干扰素特征相关的肾小管上皮细胞中免疫蛋白酶体亚基LMP7上调。
结论
我们的数据表明，I型干扰素可能在以α干扰素对肾小管上皮细胞的自分泌效应为特征的狼疮性肾炎中起致病作用。因此，我们假设抑制I型干扰素可能是预防狼疮性肾炎患者肾小管间质损伤的治疗靶点。
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