Critical role of IRF-5 in regulation of B-cell differentiation
| Autor: | Runqing Lu, David L. Huso, Paula M. Pitha, Chunyang Lien, Ferenc Livak, Chee-Mun Fang |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Cellular differentiation Antigens CD19 Plasma Cells Plasma cell CD19 Cell Line Mice Plasma cell differentiation PRDM1 medicine Animals Humans Promoter Regions Genetic Transcription factor B cell Mice Knockout B-Lymphocytes Binding Sites Multidisciplinary biology Interleukin-6 Reverse Transcriptase Polymerase Chain Reaction Age Factors Cell Differentiation Biological Sciences Flow Cytometry Molecular biology Mice Inbred C57BL medicine.anatomical_structure Cell culture Interferon Regulatory Factors Splenomegaly biology.protein Female Positive Regulatory Domain I-Binding Factor 1 Spleen Transcription Factors |
| Zdroj: | Proceedings of the National Academy of Sciences. 107:4664-4668 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | IFN-regulatory factor 5 (IRF-5), a member of the IRF family, is a transcription factor that has a key role in the induction of the antiviral and inflammatory response. When compared with C57BL/6 mice, Irf5 −/− mice show higher susceptibility to viral infection and decreased serum levels of type I IFN and the inflammatory cytokines IL-6 and TNF-α. Here, we demonstrate that IRF-5 is involved in B-cell maturation and the stimulation of Blimp-1 expression. The Irf5 −/− mice develop an age-related splenomegaly, associated with a dramatic accumulation of CD19 + B220 − B cells and a disruption of normal splenic architecture. Splenic B cells from Irf5 −/− mice also exhibited a decreased level of plasma cells. The CD19 + Irf5 −/− B cells show a defect in Toll-like receptor (TLR) 7- and TLR9-induced IL-6 production, and the aged Irf5 −/− mice have decreased serum levels of natural antibodies; however, the antigen-specific IgG1 primary response was already dependent in IRF-5 in young mice, although the IgM response was not. Analysis of the profile of transcription factors associated with plasma cell differentiation shows down-regulation of Blimp-1 expression, a master regulator of plasma cell differentiation, which can be reconstituted with ectopic IRF-5. IRF-5 stimulates transcription of the Prdm1 gene encoding Blimp-1 and binds to the IRF site in the Prdm1 promoter. Collectively, these results reveal that the age-related splenomegaly in Irf5 −/− mice is associated with an accumulation of CD19 + B220 − B cells with impaired functions and show the role of IRF-5 in the direct regulation of the plasma cell commitment factor Blimp-1 and in B-cell terminal differentiation. |
| Databáze: | OpenAIRE |
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