Genomic view of IFN-alpha response in pre-autoimmune NZB/W and MRL/lpr mice.
Interferon (IFN)-alpha is involved in the pathogenesis of systemic lupus erythematosus. Studies in murine lupus models have revealed that type I IFN exerts either a protective effect in MRL/lpr, or can detrimentally impact disease progression, as in NZB/W mice. To understand this paradox, we examined the kinetic global gene expression in pre-autoimmune NZB/W-, MRL/lpr- and normal BALB/c-derived splenic mononuclear cells following ex vivo IFN-alpha treatment. Analysis of IFN-alpha-induced gene expression patterns revealed genes associated with antiproliferative activity of IFN-alpha including CDKN1A, GADD45B, pituitary tumor-transforming 1, SCOTIN, ataxia telangiectasia-mutated homolog and calcyclin-binding protein were upregulated in MRL/lpr and/or BALB/c mice. Of IFN-alpha-induced genes differentially expressed in NZB/W vs BALB/c and MRL/lpr mice at 3 h time point, enhanced expression of CCND1, cyclin D2, matrix metalloproteinase 13 and a panel of cytokines and chemokines and impaired expression of negative inflammatory regulators CD69 and an Src family kinase hemopoietic cell kinase were notable. Interestingly, the splenic mononuclear cells from the NZB/W not MRL/lpr lupus-prone mice at the pre-autoimmune stage before ex vivo IFN-alpha treatment, have increased expression of many known IFN-regulated genes. These results provide a unique genomic view of ex vivo IFN-alpha response in two lupus-prone models, and help to have an insight into the role of IFN-alpha in lupus pathogenesis.
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Joint Molecular Rheumatology Laboratory of Institute of Health Sciences and Shanghai RenJi Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai JiaoTong University School of Medicine, Shanghai, China.
Shen
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Li
X M
XM
Chen
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SL
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007370:Interferon Type I / Q000276:immunology / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D020411:Oligonucleotide Array Sequence Analysis; D011994:Recombinant Proteins; D015398:Signal Transduction
D007370:Interferon Type I; D011994:Recombinant Proteins