Critical role of IRF-5 in regulation of B-cell differentiation.
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-alpha. 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.
Lien
Chunyang
C
Departments of Biology and Comparative Medicine, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21218, USA.
Fang
Chee-Mun
CM
Huso
David
D
Livak
Ferenc
F
Lu
Runqing
R
Pitha
Paula M
PM
D000367:Age Factors; D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation; D002460:Cell Line; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics
D018941:Antigens, CD19; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D015850:Interleukin-6; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1