Anti-inflammatory roles of microRNA 21 in lipopolysaccharide-stimulated human dental pulp cells
Anti-inflammatory roles of microRNA 21 in lipopolysaccharide-stimulated human dental pulp cells
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DOI：
10.1002/jcp.28737
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Okiji, Takashi
中科院分区：
文献类型：
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作者：
Nara, Keisuke;Kawashima, Nobuyuki;Okiji, Takashi
microRNA是一种非编码的小分子RNA，可调控RNA沉默和转录后基因表达，许多microRNA参与炎症过程。特别是，microRNA 21（miR-21）在炎症环境中上调，并报道诱导抗炎反应。然而，miR-21参与牙髓炎症以及miR-21诱导的抗炎反应的确切机制仍不清楚。我们假设miR-21- 5 p在脂多糖（LPS）刺激的人牙髓细胞（hDPC）中被诱导表达，并且miR-21- 5 p下调LPS刺激的hDPC中的促炎细胞因子表达。我们发现miR-21- 5 p在LPS刺激的hDPC中上调，伴随着促炎细胞因子表达和核因子-κ B（NF-κ B）磷酸化的升高。miR-21- 5 p和细胞因子表达被BAY 11 -7085和咖啡酸苯乙酯（CAPE）下调，这是特异性和有效的NF-κ B抑制剂。miR-21- 5 p的增强表达通过降低TNF受体相关因子6（TRAF 6）和程序性细胞死亡4（PDCD 4）的表达下调Toll样受体（TLR）/NF-κ B信号传导，从而进一步诱导促炎细胞因子表达的降低。强制过表达miR-21- 5 p的hDPC下调LPS诱导的TNF受体相关因子6（TRAF 6; Toll样受体[TLR]/NF-κ B信号通路的组分）、程序性细胞死亡4（PDCD 4，TLR/NF-κ B信号通路的正调节因子）和促炎性细胞因子的表达。相反，miR-21- 5 p转染的hDPC在LPS刺激后上调TRAF 6、PDCD 4和炎性细胞因子的表达。这些发现表明，miR-21- 5 p的表达是由NF-κ B信号通路诱导的，而NF-κ B信号通路又通过下调LPS刺激的hDPC中的TRAF 6和PDCD 4表达而受到miR-21- 5 p的负调控。
microRNAs are small noncoding RNA molecules that regulate RNA silencing and posttranscriptional gene expression, and many microRNAs are involved in inflammatory processes. In particular, microRNA 21 (miR-21) is upregulated in inflammatory environment and reported to induce anti-inflammatory responses. However, the involvement of miR-21 in pulpal inflammation and the precise mechanisms of anti-inflammatory reactions induced by miR-21 remain unclear. We hypothesized that miR-21-5p expression is induced in lipopolysaccharide (LPS)-stimulated human dental pulp cells (hDPCs) and that miR-21-5p downregulates the proinflammatory cytokine expression in LPS-stimulated hDPCs. We found that miR-21-5p was upregulated in LPS-stimulated hDPCs concomitant with elevated proinflammatory cytokine expression and nuclear factor-kappa B (NF-kappa B) phosphorylation. miR-21-5p and cytokine expression were downregulated by BAY11-7085 and caffeic acid phenylethyl ester (CAPE), specific and potent NF-kappa B inhibitors. Enforced expression of miR-21-5p downregulated the Toll-like receptor (TLR)/NF-kappa B signaling via reducing the expression of TNF receptor-associated factor 6 (TRAF6) and programmed cell death 4 (PDCD4), which further induced the decrease of proinflammatory cytokine expression. hDPCs forcibly overexpressing miR-21-5p downregulated the LPS-induced expression of TNF receptor-associated factor 6 (TRAF6; a component of the Toll-like receptor [TLR]/NF-kappa B signaling pathway), programmed cell death 4 (PDCD4, a positive regulator of the TLR/NF-kappa B signaling pathway), and proinflammatory cytokines. In contrast, miR-21-5p inhibitor-transfected hDPCs upregulated the expression of TRAF6, PDCD4, and inflammatory cytokines following LPS stimulation. These findings suggest that miR-21-5p expression was induced by the NF-kappa B signaling pathway, which was in turn negatively regulated by miR-21-5p via downregulation of TRAF6 and PDCD4 expression in LPS-stimulated hDPCs.