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A Role for c-fos/Activator Protein 1 in B Lymphocyte Terminal Differentiation¹

Yusuke Ohkubo^*,, Masafumi Arima^*, Eggi Arguni^*, Seiji Okada, Kimihiro Yamashita^*, Sadaki Asari^*, Shintaro Obata^*, Akemi Sakamoto^*, Masahiko Hatano^*, Jiyang O-Wang, Masaaki Ebara, Hiromitsu Saisho and Takeshi Tokuhisa^2,*

Departments of^* Developmental Genetics (H2) and Medicine and Clinical Oncology (K1), Graduate School of Medicine, Chiba University, Chiba, Japan; Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan; and Laboratory for B Lymphocyte Function, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, Yokohama, Kanagawa 230-0045, Japan

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.

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