Differentiation MicroRNA-21 during Plasma Cell BLIMP-1 and STAT3 Counterregulate

During cellular differentiation, mRNA transcription and translation require precise coordination. The mechanisms controlling this are not well defined. IL-21 is an important regulator of plasma cell differentiation, and it controls the master regulator of plasma cell differentiation, B lymphocyte-induced maturation protein-1 (BLIMP-1), via STAT3 and IRF4. Among the other targets of STAT3 is microRNA-21 (miR-21). miR-21 is the most frequently deregulated microRNA in malignancy, including B cell lymphomas, and it has oncogenic potential downstream of STAT3. However, the regulation and function of miR-21 during plasma cell differentiation are not characterized. In contrast to the induction of miR-21 observed in response to STAT3 activation in other systems, we demonstrate that miR-21 is repressed during IL-21–driven plasma cell differentiation. We explored the molecular basis for this repression and identify primary miR-21 transcription as a direct target of BLIMP-1–dependent repression , despite continued STAT3 activation and phospho-STAT3 binding to the primary miR-21 promoter. Thus, STAT3 and BLIMP-1 constitute an incoherent feed-forward loop downstream of IL-21 that can coordinate microRNA with mRNA expression during plasma cell differentiation. D uring the humoral immune response, both short-lived and long-lived Ab-secreting cells are made, and both require B lymphocyte-induced maturation protein-1 (BLIMP-1) expression (1). In response to Ag and follicular T cell help, B cells form germinal centers that generate high-affinity long-lived plasma cells. IL-21, which is produced by T follicular helper cells, is a potent inducer of class-switch recombination and plasma cell differentiation (2, 3). The effect of IL-21 on responsive B cells is mediated by the activation of STAT3, which, in conjunction with IRF4, results in the upregulation of BLIMP-1 (4, 5). The importance of STAT3 during plasma cell differentiation is further demonstrated by the selective loss of T-dependent IgG responses in mice that have Stat3-deficient B cells (6). Beyond its role in lymphocyte differentiation, STAT3 has been identified as part of a regulatory circuit linking inflammatory responses to cellular transformation. In this context, STAT3 was shown to directly activate microRNA-21 (miR-21) (7). Aberrant expression of microRNAs is a feature of malignancies, and microRNA profiles can define disease groups (8). Expression of miR-21 is part of the characteristic profile in diffuse large B cell lymphoma (DLBCL) (9–11). miR-21 is also overexpressed in malignant plasma cells in which expression of miR-21 is dependent on IL-6 (12, 13). Mature microRNAs are derived from processed primary transcripts , whose expression is driven predominantly from polymerase-II promoters (14). This …