A role for c-fos/activator protein 1 in B lymphocyte terminal differentiation.
Expression of B lymphocyte-induced maturation protein 1 (Blimp-1) transcription factor is essential for promoting B cell differentiation into plasma cells. However, a critical transcription factor for Blimp-1 expression in activated B cells is unclear. When splenic B cells were stimulated with CD40 ligand (CD40L) and IL-4, terminal differentiation was induced in the B cells from c-fos transgenic (H2-c-fos) mice but barely in those from control littermates and from c-fos-deficient mice. AP-1 family and Blimp-1 mRNAs were transiently induced in the control B cells, and overexpression of c-Fos induced a sufficient amount of Blimp-1 for terminal differentiation in the H2-c-fos B cells. When normal and c-fos-deficient B cells were stimulated with LPS, a sufficient amount of Blimp-1 for terminal differentiation was induced in those B cells. However, expression of c-fos/AP-1 family mRNAs in LPS-stimulated normal B cells was similar to that of normal B cells stimulated with CD40L and IL-4. EMSA and chromatin immunoprecipitation assays using the AP-1-binding DNA sequence in the murine Blimp-1 promoter region demonstrated that AP-1-binding activity in nuclear protein of LPS-stimulated normal B cells was prolonged more than that in normal B cells stimulated with CD40L and IL-4. Furthermore, the percentage of CD138(+) B cells within germinal center B cells in the spleen and the number of Ab-forming cells in the bone marrow of H2-c-fos mice was larger than that of control mice 12 days after immunization. Thus, although c-Fos is not essential for Blimp-1 expression, c-Fos/AP-1 positively regulates Blimp-1 expression and terminal differentiation of activated B cells.
Ohkubo
Yusuke
Y
Department of Developmental Genetics (H2), Graduate School of Medicine, Chiba University, Chiba, Japan.
Arima
Masafumi
M
Arguni
Eggi
E
Okada
Seiji
S
Yamashita
Kimihiro
K
Asari
Sadaki
S
Obata
Shintaro
S
Sakamoto
Akemi
A
Hatano
Masahiko
M
O-Wang
Jiyang
J
Ebara
Masaaki
M
Saisho
Hiromitsu
H
Tokuhisa
Takeshi
T
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D023201:CD40 Ligand / Q000494:pharmacology; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D018985:Epitopes, B-Lymphocyte; D008070:Lipopolysaccharides; C513258:Prdm1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D012097:Repressor Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D023201:CD40 Ligand; D015847:Interleukin-4; D000074462:Positive Regulatory Domain I-Binding Factor 1