Non-Transcriptional and Translational Function of Canonical NF-κB Signaling in Activating ERK1/2 in IL-1β-Induced COX-2 Expression in Synovial Fibroblasts.
Non-Transcriptional and Translational Function of Canonical NF-κB Signaling in Activating ERK1/2 in IL-1β-Induced COX-2 Expression in Synovial Fibroblasts.
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DOI：
10.3389/fimmu.2020.579266
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发表时间：
2020
影响因子：
7.3
通讯作者：
Sugiya H
中科院分区：
文献类型：
--
作者：
Nakano R;Kitanaka T;Namba S;Kitanaka N;Suwabe Y;Konno T;Yamazaki J;Nakayama T;Sugiya H
促炎症细胞因子白介素1β(IL-1β)通过上调类风湿关节炎(RA)等自身免疫性疾病患者滑膜组织中环氧合酶-2(COX-2)的表达，诱导前列腺素E_2的合成。IL-1β介导的NF-κB和MAPK信号通路的刺激在RA的发病机制中起重要作用；然而，NF-κB和MAPK信号之间的串扰(S)仍有待了解。在本研究中，我们建立了IL-1β诱导的滑膜炎症模型，并探讨了核因子-κB和丝裂原活化蛋白激酶信号在滑膜炎症中的作用。我们观察到经IL-1β处理的细胞COX-2mRNA和蛋白水平增加，前列腺素E_2释放增加。NF-κB和ERK1/2抑制剂显著降低IL-1β诱导的COX-2表达。IL-1β可诱导典型的NF-κB复合体(p65和p105)的磷酸化和IκBα的降解。IL-1β也可诱导ERK1/2的磷酸化，但不影响p38MAPK和JNK的磷酸化水平。IL-1β不能诱导p65、p105、ERK1或ERK2siRNA表达COX-2。值得注意的是，NF-κB抑制剂降低了IL-1β诱导的ERK1/2的磷酸化；然而，ERK1/2抑制剂对典型的NF-κB复合体的磷酸化没有影响。尽管转录和翻译抑制剂对IL-1β诱导的ERK1/2的磷酸化没有影响，但在siRNA转基因的成纤维细胞中，规范的NF-κB复合体的沉默阻止了IL-1β诱导的ERK1/2的磷酸化。综上所述，我们的研究结果表明，规范的NF-κB的非转录/翻译活性在激活ERK1/2信号通路中具有重要作用，该信号参与了IL-1β诱导的影响滑膜组织的自身免疫性疾病的发展，如RA。
The pro-inflammatory cytokine interleukin 1β (IL-1β) induces the synthesis of prostaglandin E2 by upregulating cyclooxygenase-2 (COX-2) in the synovial tissue of individuals with autoimmune diseases, such as rheumatoid arthritis (RA). IL-1β-mediated stimulation of NF-κB and MAPK signaling is important for the pathogenesis of RA; however, crosstalk(s) between NF-κB and MAPK signaling remains to be understood. In this study, we established a model for IL-1β-induced synovitis and investigated the role of NF-κB and MAPK signaling in synovitis. We observed an increase in the mRNA and protein levels of COX-2 and prostaglandin E2 release in cells treated with IL-1β. NF-κB and ERK1/2 inhibitors significantly reduced IL-1β-induced COX-2 expression. IL-1β induced the phosphorylation of canonical NF-κB complex (p65 and p105) and degradation of IκBα. IL-1β also induced ERK1/2 phosphorylation but did not affect the phosphorylation levels of p38 MAPK and JNK. IL-1β failed to induce COX-2 expression in cells transfected with siRNA for p65, p105, ERK1, or ERK2. Notably, NF-κB inhibitors reduced IL-1β-induced ERK1/2 phosphorylation; however, the ERK1/2 inhibitor had no effect on the phosphorylation of the canonical NF-κB complex. Although transcription and translation inhibitors had no effect on IL-1β-induced ERK1/2 phosphorylation, the silencing of canonical NF-κB complex in siRNA-transfected fibroblasts prevented IL-1β-induced phosphorylation of ERK1/2. Taken together, our data indicate the importance of the non-transcriptional/translational activity of canonical NF-κB in the activation of ERK1/2 signaling involved in the IL-1β-induced development of autoimmune diseases affecting the synovial tissue, such as RA.
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影响因子：
6
作者：
Christian F;Smith EL;Carmody RJ
通讯作者：
Carmody RJ
影响因子：
4.8
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Jiang, BB;Xu, SQ;Cohen, RA
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Cohen, RA
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De Smaele, E;Zazzeroni, F;Franzoso, G
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Kitanaka, Nanako;Nakano, Rei;Sugiya, Hiroshi
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