title: 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.affiliation: Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research (FIMR), Manhasset, New York, USA.
authors.forename: Sun Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Peter K
authors.initials: PK
authors.lastname: Gregersen
authors.forename: Betty
authors.initials: B
authors.lastname: Diamond
mesh_terms: D000818:Animals; D001483:Base Sequence; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D008875:Middle Aged; D018448:Models, Immunological; D008969:Molecular Sequence Data; D010641:Phenotype; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D016207:Cytokines; D035683:MicroRNAs; C513258:Prdm1 protein, mouse; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; C542687:mirnlet7 microRNA, mouse; C087042:PRDM1 protein, human; D000074462:Positive Regulatory Domain I-Binding Factor 1