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Role of interferon-alpha in the activation of tubular epithelial cell in lupus nephritis (LN)

ABSTRACT: Plasmacytoid dendritic cells (pDCs) play a key role in the activation of the autoimmune response in LN. Recently we demonstrated that these cells infiltrate the kidney of patients with LN at tubulointerstitial level. The pDCs are the main producers of IFN-alpha, whose effects on the renal tubule are poorly understood. The aim of the study was to investigate the effects of INF-alpha in renal epithelial cells (RPTEC). We investigated the effect of IFN-alpha on the whole-genome gene expression profile in RPTEC cells,. Genomic analysis showed that after stimulation, 108 genes are up-regulated and only 7 are down-regulated, with a fold-change> 2. The Gene Set Enrichment analysis confirmed that IFN-alpha induced the pathway of antigen presentation and the inflammatory signaling in RPTEC. Among the up-regulated genes involved in these pathways, there were HLA-I, the ubiquitins (FBXO6 and DTX3L) and the immunoproteasome subunits LMP7. We performed the validation of these genes by real time PCR and citometry experiments on RPTEC stimulated with IFN-alpha. Immunohistochemical analysis of LMP7 and MXA protein, specific marker of IFN-alpha, showed a significant upregulatation of both proteins in renal biopsies of patients with LN class IV compared to class I. Confocal microscopy showed the colocalization of LMP7-MXA in tubular epithelium of patients with LN class IV and activation of inflammatory signaling via NF-kB in the MXA+ tubules. Our data suggested that inhibition of INF-alpha pathways could represent a novel therapeutic strategy to reduce renal tubular damage in patients with LN.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48551 | GEO | 2015/12/15

SECONDARY ACCESSION(S): PRJNA210614

REPOSITORIES: GEO

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Role of interferon-alpha in the activation of tubular epithelial cell in lupus nephritis (LN)

Project description:Plasmacytoid dendritic cells (pDCs) play a key role in the activation of the autoimmune response in LN. Recently we demonstrated that these cells infiltrate the kidney of patients with LN at tubulointerstitial level. The pDCs are the main producers of IFN-alpha, whose effects on the renal tubule are poorly understood. The aim of the study was to investigate the effects of INF-alpha in renal epithelial cells (RPTEC). We investigated the effect of IFN-alpha on the whole-genome gene expression profile in RPTEC cells,. Genomic analysis showed that after stimulation, 108 genes are up-regulated and only 7 are down-regulated, with a fold-change> 2. The Gene Set Enrichment analysis confirmed that IFN-alpha induced the pathway of antigen presentation and the inflammatory signaling in RPTEC. Among the up-regulated genes involved in these pathways, there were HLA-I, the ubiquitins (FBXO6 and DTX3L) and the immunoproteasome subunits LMP7. We performed the validation of these genes by real time PCR and citometry experiments on RPTEC stimulated with IFN-alpha. Immunohistochemical analysis of LMP7 and MXA protein, specific marker of IFN-alpha, showed a significant upregulatation of both proteins in renal biopsies of patients with LN class IV compared to class I. Confocal microscopy showed the colocalization of LMP7-MXA in tubular epithelium of patients with LN class IV and activation of inflammatory signaling via NF-kB in the MXA+ tubules. Our data suggested that inhibition of INF-alpha pathways could represent a novel therapeutic strategy to reduce renal tubular damage in patients with LN. To identify genes specifically modulated by INF-alpha in RPTEC, we stimulated 3 different cell clones with 100U/ml INF-alpha for 48 hours and compared their whole-genome gene expression profiles with that from 3 RPTEC clones cultured without stimuli.

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Identification of long noncoding RNA RP11-2B6.2 as a positive regulator of type I interferon pathway in lupus nephritis

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