Regulation of dendritic cell activation by microRNA let-7c and BLIMP1

被引:74
|
作者
Kim, Sun Jung [1 ]
Gregersen, Peter K. [2 ]
Diamond, Betty [1 ]
机构
[1] Feinstein Inst Med Res, Ctr Autoimmune & Musculoskeletal Dis, Manhasset, NY 11030 USA
[2] Feinstein Inst Med Res, Robert S Boas Ctr Genom & Human Genet, Manhasset, NY 11030 USA
关键词
TRANSCRIPTIONAL REPRESSOR BLIMP-1; SYSTEMIC-LUPUS-ERYTHEMATOSUS; SECRETING PLASMA-CELLS; SELF-TOLERANCE; RISK LOCI; T-CELLS; B-CELLS; AUTOIMMUNITY; DIFFERENTIATION; LYMPHOCYTES;
D O I
10.1172/JCI64712
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Mice with a DC-specific deletion of the transcriptional repressor B lymphocyte-induced maturation protein-1 (Blimp1) exhibit a lupus-like phenotype, secondary to enhanced DC production of IL-6. Here we explored further phenotypic changes in Blimp1-deficient DCs, the molecular mechanism underlying these changes, and their relevance to human disease. Blimp1-deficient DCs exhibited elevated expression of MHC II, and exposure to TLR agonists increased secretion of proinflammatory cytokines. This phenotype reflects enhanced expression of the microRNA let-7c, which is regulated by BLIMP1. Let-7c reciprocally inhibited Blimp1 and also blocked LPS-induced suppressor of cytokine signaling-1 (SOCS1) expression, contributing to the proinflammatory phenotype of Blimp1-deficient DCs. DCs from Blimp1 SLE-risk allele carriers exhibited analogous phenotypic changes, including decreased BLIMP1 expression, increased let-7c expression, and increased expression of proinflammatory cytokines. These results suggest that let-7c regulates DC phenotype and confirm the importance of BLIMP1 in maintaining tolerogenic DCs in both mice and humans.
引用
收藏
页码:823 / 833
页数:11
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