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

Abstract

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.

Epidermal terminal differentiation depends on B lymphocyte-induced maturation protein-1

“…Binding of Blimp-1 to a site in intron 2 of the gene (Fig. 4) provides evidence of direct repression, whereas repression of fos is predicted to decrease the levels of AP-1, an activator of prdm1 (23). Although the biological significance of autorepression is not clear, Blimp-1 can be toxic (24), and we have subsequently also observed autoregulation in the T cell lineage (K.C.…”

Plasmacytic Transcription Factor Blimp-1 Is Repressed by Bach2 in B Cells

“…Because the promoter MARE has been reported to be an AP-1 binding site (16), AP-1 may function as an activator of the promoter MARE. Indeed, c-Fos has been implicated in the activation of Prdm1 in B cells (44). The small Maf proteins are dual function factors that either repress or activate transcription, depending on their partners (20).…”

Decoy oligodeoxynucleotide targeting activator protein-1 (AP-1) attenuates intestinal inflammation in murine experimental colitis

“…Treatment with AP-1 or NF-kB decoy ODN significantly decreased IL-1b, TNF-a, and MPO activities in the tissue contents, which coincided well with the results of our histological examinations (Figure 6a-c). [33][34][35][36][37][38][39][40] Although AP-1 is a major immunoregulatory as well as proinflammatory transcription factor, 21,[27][28][29][30][45][46][47] nothing is known to have been reported regarding the effect of AP-1 inhibition by a decoy ODN on intestinal inflammation. In the present study, we designed a ds decoy ODN binding to AP-1-specific nucleotide sequences and investigated its efficacy to prevent murine experimental DSS-induced colitis.…”

“…On the other hand, AP-1 has also been recognized to play important roles in cell proliferation, migration, and differentiation in various organs. 21,[27][28][29][30] Particularly, epithelial proliferation and migration are essential steps in the healing process of intestinal inflammation, which is regulated by a variety of AP-1-mediated genes. Therefore, blockade of AP-1-mediated signaling may influence mucosal regeneration during the healing of chronic intestinal inflammation including IBD, whereas the appropriate dosage period of AP-1 decoy ODN should be carefully evaluated for future clinical applications.…”

“…[24][25][26] AP-1 binds to specific DNA sequences present in a large number of genes that regulate inflammation, cellular growth, and differentiation. 21,[27][28][29][30] Several agents that suppress AP-1 activation have been shown to inhibit inflammation and tumorigenesis. Recent studies have demonstrated that AP-1 is one of the key transcription factors that upregulate genes involved in immune as well as proinflammatory responses during the pathogenesis of IBD, suggesting that AP-1 may be an ideal target for the development of new therapeutic options for IBD.…”