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Significance of Polymorphism and Expression of miR-146a and NFkB1 Genetic Variants in Patients with Rheumatoid Arthritis.

ABSTRACT: MicroRNA-146a (miR-146a) has been shown to play an important role in the regulation of inflammatory innate immune responses, and found to be differentially expressed in rheumatoid arthritis (RA). Through NF-?B pathway, this molecule is able to stimulate the release of pro-inflammatory cytokines such as TNF-?, IL-1?, and IL-17. It has been also suggested that single-nucleotide polymorphisms (SNPs) in miRNA sequences may alter miRNA expression and that miR-146a rs2910164 SNP may contribute to RA development. These observations prompted us to analyze the potential associations between the miR-146a-3p (rs2910164, G > C) and NFkB1 (rs28362491, ins/del ATTG) polymorphisms and miR-146a-5p expression in patients' sera in relation to clinical outcome of the treatment as well as predisposition to RA. Genotyping was performed in 111 patients and 130 healthy individuals while 16 controls and 13 RA patients (before and after three months of therapy with TNF-? inhibitors (TNFi)) were studied for the circulating miR-146a-5p serum expression level. Patients carrying the NFkB1 ins/ins genotype were characterized by worse response to TNFi treatment (p = 0.023). In patients, before TNFi therapy, expression levels of miR-146a-5p were less (0.422 ± 0.171) as compared to those detected after three months of treatment (1.809 ± 0.658, p = 0.033) and observed for healthy controls (5.302 ± 2.112, p = 0.048). Moreover, patients with higher circulating miR-146a-5p levels after three months of TNFi administration were more frequently carrying the rs2910164-C allele (p = 0.032). These results support the hypothesis that miR-146a might be involved in pathogenesis of RA and imply that miR-146a-3p polymorphism may be associated with miR-146a-5p levels in serum after anti-TNF-? treatment.

SUBMITTER: Bogunia-Kubik K

PROVIDER: S-EPMC5334424 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Significance of Polymorphism and Expression of miR-146a and NFkB1 Genetic Variants in Patients with Rheumatoid Arthritis.

Bogunia-Kubik Katarzyna K Wysoczańska Barbara B Piątek Dagmara D Iwaszko Milena M Ciechomska Marzena M Świerkot Jerzy J

Archivum immunologiae et therapiae experimentalis 20161201 Suppl 1

MicroRNA-146a (miR-146a) has been shown to play an important role in the regulation of inflammatory innate immune responses, and found to be differentially expressed in rheumatoid arthritis (RA). Through NF-κB pathway, this molecule is able to stimulate the release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-17. It has been also suggested that single-nucleotide polymorphisms (SNPs) in miRNA sequences may alter miRNA expression and that miR-146a rs2910164 SNP may contribute to RA d ...[more]

PMID: 28083614

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Project description:BackgroundAngiogenesis is a major contributor to the development of inflammation during Rheumatoid arthritis (RA), as the vascularization of the pannus provides nutrients and oxygen for the infiltrating immune cells and proliferating synoviocytes. Tocilizumab (TCZ) is an anti-IL-6 receptor antibody that is used in the treatment of RA patients, and has been shown to exert anti-inflammatory effects. However, its effects on angiogenesis are not fully elucidated, and the molecular mechanisms regulating this effect are unknown.MethodsWe evaluated the concentrations of several pro- and anti-angiogenic factors and the expression levels of several microRNA molecules that are associated with RA and angiogenesis in serum samples obtained from 40 RA patients, before and 4 months after the initiation of TCZ treatment. Additionally, we used an in vitro co-culture system of fibroblasts (the HT1080 cell line) and monocytes (the U937 cell line) to explore the mechanisms of TCZ action.ResultsSerum samples from RA patients treated with TCZ exhibited reduced circulating levels of EMMPRIN/CD147, enhanced expression of circulating miR-146a-5p and miR-150-5p, and reduced the angiogenic potential as was manifested by the lower number of tube-like structures that were formed by EaHy926 endothelial cell line. In vitro, the accumulation in the supernatants of the pro-angiogenic factors EMMPRIN, VEGF and MMP-9 was increased by co-culturing the HT1080 fibroblasts and the U937 monocytes, while the accumulation of the anti-angiogenic factor thrombospondin-1 (Tsp-1) and the expression levels of miR-146a-5p were reduced. Transfection of HT1080 cells with the miR-146a-5p mimic, decreased the accumulation of EMMPRIN, VEGF and MMP-9. When we neutralized EMMPRIN with a blocking antibody, the supernatants derived from these co-cultures displayed reduced migration, proliferation and tube formation in the functional assays.ConclusionsOur findings implicate miR-146a-5p in the regulation of EMMPRIN and propose that TCZ affects angiogenesis through its effects on EMMPRIN and miR-146a-5p.

Dataset Information

Significance of Polymorphism and Expression of miR-146a and NFkB1 Genetic Variants in Patients with Rheumatoid Arthritis.

Publications

Significance of Polymorphism and Expression of miR-146a and NFkB1 Genetic Variants in Patients with Rheumatoid Arthritis.

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