title: Cell type and gender-dependent differential regulation of the p202 and Aim2 proteins: implications for the regulation of innate immune responses in SLE.
abstract: Upon sensing cytosolic double-stranded DNA (dsDNA), the murine Aim2 (encoded by the Aim2 gene) protein forms an inflammasome and promotes the secretion of proinflammatory cytokines, such as IL-1β and IL-18. In contrast, the p202 protein (encoded by the Ifi202 gene) does not form an inflammasome. Previously, we have reported that the interferon (IFN) and female sex hormone-induced increased nuclear levels of p202 protein in immune cells are associated with increased susceptibility to develop a lupus-like disease. However, signaling pathways that regulate the expression of Aim2 protein remain unknown. Here we report that the expression of Aim2 gene is induced in bone marrow-derived macrophages (BMDMs) by IFN-α treatment and the expression is, in part, STAT1-dependent. However, treatment of splenic T or B cells with IFN-α or their stimulation, which induced the expression of Ifi202 gene, did not induce the expression of Aim2 gene. Furthermore, treatment of cells with the male hormone androgen increased levels of Aim2 mRNA and protein. Moreover, treatment of murine macrophage cell lines (RAW264.7 and J774A.1) with IFN-α differentially induced the expression of Aim2 and p202 proteins and regulated their sub-cellular localization. Additionally, activation of Toll-like receptors (TLR3, 4, and 9) in BMDMs and cell lines also differentially regulated the expression of Aim2 and Ifi202 genes. Our observations demonstrate that cell type and gender-dependent factors differentially regulate the expression of the Aim2 and p202 proteins, thus, suggesting opposing roles for these two proteins in innate immune responses in lupus disease.
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, United States.
authors.forename: Ravichandran
authors.initials: R
authors.lastname: Panchanathan
authors.forename: Xin
authors.initials: X
authors.lastname: Duan
authors.forename: Muthuvel
authors.initials: M
authors.lastname: Arumugam
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Hongzhu
authors.initials: H
authors.lastname: Liu
authors.forename: Divaker
authors.initials: D
authors.lastname: Choubey
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D015151:Immunoblotting; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: C540422:Aim2 protein, mouse; D004268:DNA-Binding Proteins; C092537:Ifi202b protein, mouse; D058847:Inflammasomes; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins