Abstract
BackgroundTumor necrosis factor-alpha (TNF-α) can cause diverse T cell dysfunctions in patients with rheumatoid arthritis (RA). It is involved in the regulation of microRNAs (miRNAs) expression in different cell types. We hypothesized that the expression of T cell miRNAs would be affected by TNF-α, and these miRNAs could participate in the immunopathogenesis of RA.MethodsExpression profiles of 270 human miRNAs in Jurkat cells, cultured in the presence or absence of TNF-α for 7 days were analyzed by real-time polymerase chain reaction. Potentially aberrantly expressed miRNAs were validated using T cell samples from 35 patients with RA and 15 controls. Transfection studies were conducted to search for gene expression and biological functions regulated by specific miRNAs.ResultsInitial analysis revealed 12 miRNAs were significantly lower, whereas the expression level of miR-146a was significantly higher in Jurkat cells after being cultured with TNF-α for 7 days. Decreased expression of miR-139-3p, miR-204, miR-760, miR-524-5p, miR-136, miR-548d-3p, miR-214, miR-383, and miR-887 were noted in RA T cells. Expression levels of miR-139-3p, miR-204, miR-214, and miR-760 were correlated with the use of biologic agents. The transfection of miR-214 mimic suppressed TNF-α-mediated apoptosis of Jurkat cells. Increased phosphorylation of extracellular regulating kinase (ERK) and c-Jun N-terminal kinase (JNK) was noted in RA T cells and Jurkat cells after TNF-α exposure. Transfection of Jurkat cells with miR-214 mimic suppressed both the basal and TNF-α-mediated ERK and JNK phosphoryation.ConclusionsAmong T cell miRNAs affected by TNF-α, the expression levels of nine miRNAs were decreased in T cells from patients with RA. The expression levels of miR-139-3p, miR-204, miR-214, and miR-760 increased in RA patients receiving biologic agents. The transfection of miR-214 reversed the TNF-α-mediated cells apoptosis and inhibited the phosphorylation of ERK and JNK in Jurkat cells.
Highlights
Tumor necrosis factor-alpha (TNF-α) can cause diverse T cell dysfunctions in patients with rheumatoid arthritis (RA)
Identification of the chronic Tumor necrosis factor alpha (TNF-α) exposure affected expression of miRNAs in Jurkat cells Expression profiles of 270 miRNAs in Jurkat cells cultured in the presence or absence of TNF-α (20 ng/mL) for 7 days are displayed in Fig. 1a, with each scatter spot represents the average of three adjusted miRNA levels from each group
Expression profiles of T cell miRNAs affected by TNF-α miRNAs from patients with RA and healthy controls The purities of T cells were all greater than 98.75%, and a representative example was shown in Additional file 1: Figure S1
Summary
Tumor necrosis factor-alpha (TNF-α) can cause diverse T cell dysfunctions in patients with rheumatoid arthritis (RA) It is involved in the regulation of microRNAs (miRNAs) expression in different cell types. The presence of autoantibodies, immune complexes formation, abnormal T cell responses, T cell-independent cytokine networks, and aggressive tumor-like behavior of rheumatoid synovium are thought to be involved in the pathogenesis of RA [1]. Among these immunological dysfunctions, increased production of proinflammatory cytokines, especially tumor necrosis factor alpha (TNF-α) plays a critical role in the immunopathogenesis of RA [2]. It could contribute to the pathogenesis of RA by facilitating the Th17 differentiation, inhibiting regulatory T cells differentiation, and causing an imbalance of the pro- and anti-inflammatory cytokine as well as an abnormal activation of T cells [5]
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