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MiR-181d regulates human dendritic cell maturation through NF-?B pathway.

ABSTRACT: OBJECTIVES:MicroRNAs (miRNAs) are considered as the cellular regulators which post-transcriptionally modulate gene expression in diverse biological processes including cell development and immunity. In this study, we investigated functions of miR-181d in dendritic cells (DCs) maturation, and the underlying mechanisms were also explored. MATERIALS AND METHODS:Here we did the miRNA screening in human DCs in response to lipopolysaccharides (LPS) by quantitative real-time PCR (qRT-PCR). The expressions of DCs maturation markers were measured after miRNA mimics transfections. The pharmacological inhibitors of signalling pathways were applied to examine miR-181d effect on DCs maturation by Western blot. Luciferase assay and mixed lymphocyte reaction (MLR) were also performed to reveal the target gene of miR-181d and test the viability of T cells treated with miR-181d transfected DCs. RESULTS:Overexpression of miR-181d per se is sufficient to promote DCs maturation, and up-regulate CD80 and CD83 expressions without LPS. Besides, we showed that miR-181d activated NF-?B pathway and also promoted the expression of pro-inflammatory cytokine IL12 and TNF-?. Inhibition of NF-?B pathway suppressed DCs maturation. Luciferase reporter assay and target gene knockdown assay indicated that miR-181d targets regulator cylindromatosis (CYLD), a primary negative regulator of NF-?B pathway. MLR assay showed that miR-181d-transfected DCs could promote T-cell proliferation than iDCs in vitro. CONCLUSION:Our study demonstrates that miR-181d is required for DCs maturation through the activation of NF-?B pathway by targeting CYLD.

SUBMITTER: Su XW

PROVIDER: S-EPMC6529105 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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miR-181d regulates human dendritic cell maturation through NF-κB pathway.

Su Xian Wei XW Lu Gang G Leung Chi Kwan CK Liu Qiang Q Li Yi Y Tsang Kam Sze KS Zhao Shi Dou SD Chan Danny Tat Ming DTM Kung Hsiang Fu HF Poon Wai Sang WS

Cell proliferation 20170721 5

<h4>Objectives</h4>MicroRNAs (miRNAs) are considered as the cellular regulators which post-transcriptionally modulate gene expression in diverse biological processes including cell development and immunity. In this study, we investigated functions of miR-181d in dendritic cells (DCs) maturation, and the underlying mechanisms were also explored.<h4>Materials and methods</h4>Here we did the miRNA screening in human DCs in response to lipopolysaccharides (LPS) by quantitative real-time PCR (qRT-PCR ...[more]

PMID: 28731516

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Project description:ObjectiveIn our previous study, we identified a notable increase in miR-548ag content after obesity, which contributes to the progression of Type 2 diabetes Mellitus(T2DM) through the up-regulation of Dipeptidyl Peptidase-4(DPP4) expression within the liver. However, the precise molecular mechanisms underlying the upregulation of DPP4 by miR-548ag remain elusive. Mature miRNAs rich in GU sequences can activate the TLR(7/8)/NF-κB signalling pathway, which transcriptionally activates DPP4 expression. Notably, the proportion of GU sequences in hsa-miR-548ag was found to be 47.6%. The study proposes a hypothesis suggesting that miR-548ag could potentially increase DPP4 expression in hepatocytes by activating the TLR(7/8)/NF-κB signalling pathway.MethodsMale C57BL/6J mice were fed normal chow diet (NCD, n = 16) or high-fat diet (HFD, n = 16) for 12 weeks. For a duration of 6 weeks, NCD mice received intraperitoneal injections of a miR-548ag mimic, while HFD mice and db/db mice (n = 16) were administered intraperitoneal injections of a miR-548ag inhibitor. qRT-PCR and Western Blot were used to detect the expression level of miR-548ag, DPP4 and the activation of TLR(7/8)/NF-κB signalling pathway. HepG2 and L02 cells were transfected with miR-548ag mimic, miR-548ag inhibitor, TLR7/8 interfering fragment, and overexpression of miR-548ag while inhibiting TLR7/8, respectively.Results(1) We observed elevated levels of miR-548ag in the serum, adipose tissue, and liver of obese mice, accompanied by an upregulation of TLR7/8, pivotal protein in the NF-κB pathway, and DPP4 expression in the liver. (2) miR-548ag promotes DPP4 expression in hepatocytes via the TLR(7/8)/NF-κB signalling pathway, resulting in a reduction in the glucose consumption capacity of hepatocytes. (3) The administration of a miR-548ag inhibitor enhanced glucose tolerance and insulin sensitivity in db/db mice.ConclusionsMiR-548ag promotes the expression of DPP4 in hepatocytes by activating the TLR(7/8)/NF-κB signalling pathway. MiR-548ag may be a potential target for the treatment of T2DM.

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MiR-181d regulates human dendritic cell maturation through NF-?B pathway.

Publications

miR-181d regulates human dendritic cell maturation through NF-κB pathway.

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