title: Distinct regulation of murine lupus susceptibility genes by the IRF5/Blimp-1 axis.
abstract: Genome-wide association studies have identified lupus susceptibility genes such as IRF5 and PRDM1 (encoding for IFN regulatory factor 5 [IRF]5 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 IFN-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 C57BL/6.Nba2, New Zealand Black, and C57BL/6.Sle123 female mice (as compared with age-matched C57BL/6 female mice) was associated with increased levels of the p202 protein. Taken together, our observations demonstrate that the IRF5/Blimp-1 axis differentially regulates the expression of Nba2 lupus susceptibility genes, and they suggest an important role for the IRF5/Blimp-1/p202 axis in murine lupus susceptibility.
authors: Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA.
authors: Ravichandran
authors: R
authors: Panchanathan
authors: Hongzhu
authors: H
authors: Liu
authors: Hongqi
authors: H
authors: Liu
authors: Chee-Mun
authors: CM
authors: Fang
authors: Loren D
authors: LD
authors: Erickson
authors: Paula M
authors: PM
authors: Pitha
authors: Divaker
authors: D
authors: Choubey
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D017452:Receptors, IgG / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins; C499172:Fcgr2b protein, mouse; C092537:Ifi202b protein, mouse; D050835:Interferon Regulatory Factors; D047908:Intracellular Signaling Peptides and Proteins; C498178:Irf5 protein, mouse; D009687:Nuclear Proteins; C513258:Prdm1 protein, mouse; D017452:Receptors, IgG; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1