Department of Pulp Biology and Endodontics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8549, Japan.
Int J Mol Sci. 2023 Apr 18;24(8):7433. doi: 10.3390/ijms24087433.
MicroRNA-146b-5p (miR-146b-5p) is up-regulated during and to suppress the inflammation process, although mechanisms involved in the action of miR-146b-5p have not been fully elucidated. This study examined the anti-inflammation effects of miR-146b-5p in lipopolysaccharide (LPS)-stimulated human dental pulp cells (hDPCs). An increase in human miR-146b-5p (hsa-miR-146b-5p) expression following the mRNA expression of pro-inflammatory cytokines was observed in LPS-stimulated hDPCs. The expression of hsa-miR-146b-5p and pro-inflammatory cytokines was down-regulated by a nuclear factor-kappa B (NF-κB) inhibitor, and the expression of hsa-miR-146b-5p was also decreased by a JAK1/2 inhibitor. Enforced expression of hsa-miR-146b-5p abolished phosphorylation of NF-κB p65 and down-regulated the expression of pro-inflammatory cytokines and NF-κB signaling components, such as interleukin-1 receptor-associated kinase 1 (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), and REL-associated protein involved in NF-κB (RELA). Expression of rat miR-146b-5p (rno-miR-146b-5p) and pro-inflammatory cytokine mRNA was also up-regulated in experimentally-induced rat pulpal inflammation in vivo, and rno-miR-146b-5p blocked the mRNA expression of pro-inflammatory mediators and NF-κB signaling components in LPS-stimulated ex vivo cultured rat incisor pulp tissues. These findings suggest that the synthesis of miR-146b-5p is controlled via an NF-κB/IL6/STAT3 signaling cascade, and in turn, miR-146b-5p down-regulates the expression of pro-inflammatory mediators by targeting TRAF6, IRAK1, and RELA in LPS-stimulated hDPCs.
miR-146b-5p（miR-146b-5p）在炎症过程中上调，并抑制炎症过程，尽管 miR-146b-5p 作用的机制尚未完全阐明。本研究探讨了 miR-146b-5p 在脂多糖（LPS）刺激的人牙髓细胞（hDPCs）中的抗炎作用。在 LPS 刺激的 hDPCs 中，观察到促炎细胞因子的 mRNA 表达后，人 miR-146b-5p（hsa-miR-146b-5p）的表达增加。核因子-κB（NF-κB）抑制剂下调 hsa-miR-146b-5p 和促炎细胞因子的表达，JAK1/2 抑制剂也下调 hsa-miR-146b-5p 的表达。hsa-miR-146b-5p 的强制表达消除了 NF-κB p65 的磷酸化，并下调了促炎细胞因子和 NF-κB 信号成分的表达，如白细胞介素-1 受体相关激酶 1（IRAK1）、肿瘤坏死因子受体相关因子 6（TRAF6）和 REL 相关蛋白参与 NF-κB（RELA）。在体内实验性大鼠牙髓炎症中，大鼠 miR-146b-5p（rno-miR-146b-5p）和促炎细胞因子 mRNA 的表达也上调，并且 rno-miR-146b-5p 阻断了 LPS 刺激的体外培养大鼠切牙牙髓组织中促炎介质和 NF-κB 信号成分的 mRNA 表达。这些发现表明，miR-146b-5p 的合成是通过 NF-κB/IL6/STAT3 信号级联控制的，反过来，miR-146b-5p 通过靶向 TRAF6、IRAK1 和 RELA 下调 LPS 刺激的 hDPCs 中促炎介质的表达。
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