title: ERKs induce expression of the transcriptional repressor Blimp-1 and subsequent plasma cell differentiation.
abstract: In immune cells, the positive role of the extracellular signal-regulated kinase (ERK) signaling pathway in cell cycle progression and survival is well established; however, it is unclear whether ERK signaling plays a role in cell differentiation. Here, we report that ERKs are essential for the differentiation of B cells into antibody-producing plasma cells and that ERKs induce the expression of Prdm1, which encodes Blimp-1, a transcriptional repressor and "master regulator" of plasma cell differentiation. Transgenic mice with conditional deletion of both ERK1 and ERK2 in germinal center (GC) B cells lacked plasma cells differentiated after GC formation, and memory B cells from these mice failed to differentiate into plasma cells. In addition, ERK1- and ERK2-deficient B cells exhibited impaired Prdm1 expression upon stimulation with antibody against CD40 in the presence of interleukin-4; conversely, enforced expression of Prdm1 in ERK1- and ERK2-deficient B cells restored the generation of plasma cells. Thus, our study suggests that cytokines stimulate ERKs to induce the production of Blimp-1 and that ERKs thereby contribute to the process of cellular differentiation.
authors.affiliation: Laboratory for Lymphocyte Differentiation, Research Center for Allergy and Immunology, RIKEN, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yasuda
authors.forename: Kohei
authors.initials: K
authors.lastname: Kometani
authors.forename: Noriko
authors.initials: N
authors.lastname: Takahashi
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Imai
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Aiba
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry / Q000379:methods; D018858:Germinal Center / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000166:cytology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D017931:DNA Primers; C513258:Prdm1 protein, mouse; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D048049:Extracellular Signal-Regulated MAP Kinases