title: Inhibition of microRNA let-7i depresses maturation and functional state of dendritic cells in response to lipopolysaccharide stimulation via targeting suppressor of cytokine signaling 1.
abstract: Dendritic cells (DCs) can initiate immune responses or confer immune tolerance depending on functional status. LPS-induced DC maturation is defined by enhanced surface expression of CD80 and CD86. MicroRNAs are critical for the regulation of DC function and immunity, and the microRNA let-7i was upregulated during LPS-induced DC maturation. Downregulation of let-7i significantly impeded DC maturation as evidenced by reduced CD80 and CD86 expression. DCs stimulated by LPS promoted T cell proliferation in coculture, whereas LPS-stimulated DCs with downregulated let-7i were not effective at stimulating T cell proliferation but promoted expansion of the regulatory T cell (Treg) population. There were two subpopulations of LPS-stimulated DCs with downregulated let-7i, CD86(-) and CD86(+), and it was the CD86(-) DCs that were more effective in inducing T cell hyporesponsiveness and enhancing Treg numbers, indicating that this DC population had tolerogenic properties. Furthermore, Tregs with upregulated IL-10 underscored the tolerogenic effect of CD86(-) DCs. Suppressor of cytokine signaling 1 (SOCS1), a crucial mediator of DC maturation, was confirmed as a let-7i target gene by luciferase construct assay. Suppression or overexpression of let-7i caused reciprocal alterations in SOCS1 protein expression, but had no significant effects on SOCS1 mRNA levels, indicating that let-7i regulated SOCS1 expression by translational suppression. The modulation of SOCS1 protein by let-7i was mainly restricted to CD86(-) DCs. Our study demonstrates that let-7i regulation of SOCS1 is critical for LPS-induced DC maturation and immune function. Dynamic regulation of let-7i may fine-tune immune responses by inducing Ag-specific immune tolerance.
authors: Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin Medical University, Harbin, Heilongjiang Province 150081, China.
authors: Maomao
authors: M
authors: Zhang
authors: Fang
authors: F
authors: Liu
authors: Haibo
authors: H
authors: Jia
authors: Qi
authors: Q
authors: Zhang
authors: Li
authors: L
authors: Yin
authors: Wei
authors: W
authors: Liu
authors: Hulun
authors: H
authors: Li
authors: Bo
authors: B
authors: Yu
authors: Jian
authors: J
authors: Wu
mesh_terms: D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497966:Cd86 protein, rat; D008070:Lipopolysaccharides; D035683:MicroRNAs; C491589:Socs1 protein, rat; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins