Regulation of dendritic cell activation by microRNA let-7c and BLIMP1
Sun Jung Kim, … , Peter K. Gregersen, Betty Diamond
Sun Jung Kim, … , Peter K. Gregersen, Betty Diamond
Published January 9, 2013
Citation Information: J Clin Invest. 2013;123(2):823-833. https://doi.org/10.1172/JCI64712.
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Research Article Autoimmunity

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

Abstract

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.

Authors

Sun Jung Kim, Peter K. Gregersen, Betty Diamond

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Figure 3

Regulation of SOCS1 by let-7c in DCs and defective induction in Blimp1-deficient DCs.

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Regulation of SOCS1 by let-7c in DCs and defective induction in Blimp1-d...
(A) Regulation of expression of SOCS1 mediated by let-7c was measured by luciferase assay. One microgram of SOCS1/luciferase vector alone or with 1.4 μg of either let-7c or control miRNA-expressing vectors was transfected into the 293 cell line. Luciferase activity was measure at 48 hours after transfection by luminometer. The graph represents the mean ± SEM of 3 independent experiments. Induction of SOCS1 from splenic DCs (B) or BM-DCs (D) was measured by Western blotting. (C) Quantification of SOCS1 bands from the data of splenic DCs in (B) was performed by densitometry, and the graph depicts the mean ± SEM of 3 independent experiments. DCs were purified and stimulated with LPS for 24 hours (splenic DCs) or for various durations (BM-DCs). A proteosomal inhibitor, MG-132 (25 μM), was added 3 hours before harvest to prevent degradation of SOCS1. A representative image of 3 independent experiments is shown.