Critical role of IL-1 in IL-1-induced inflammatory responses: cooperation with NF-Bp65 in transcriptional regulation
Critical role of IL-1 in IL-1-induced inflammatory responses: cooperation with NF-Bp65 in transcriptional regulation
复制标题
DOI：
10.1096/fj.201801513r
复制
发表时间：
2019-02-01
期刊：
影响因子：
4.8
通讯作者：
Ahmed, Salahuddin
中科院分区：
文献类型：
--
作者：
Singh, Anil K.;Fechtner, Sabrina;Ahmed, Salahuddin
IL-1细胞因子被认为是协调急性和慢性炎性疾病的第一个细胞因子家族。IL-1和IL-1都是IL-1家族的成员;然而，它们在炎症过程中的独特作用仍然知之甚少。我们探讨了IL-1在IL-1激活的信号通路中引起类风湿关节炎（RA）滑膜炎症的作用。使用从RA关节分离的滑膜成纤维细胞，我们发现IL-1显著刺激IL-1表达，通过阻断NF-B通路选择性抑制IL-1表达。使用小干扰RNA敲低IL-1消除IL-1诱导的pro-IL-1和pro-IL-1表达并抑制炎症。天然和染色质免疫沉淀研究表明，IL-1协同NF-Bp 65与IL-1启动子的远端区域和转录起始位点上游的IL-1启动子的近端区域结合，以稳定它们的基因转录。IL-1或IL-1与IL-1受体结合的分子动力学模拟显示出不同的相互作用位点，这证实了IL-1与IL-1相比差异激活信号蛋白磷酸化的能力。我们的研究强调了IL-1在介导IL-1诱导的炎症中的重要性，除了维持其表达并提供靶向IL-1以最小化IL-1在炎性疾病如RA中的作用的基本原理。K.，Fechtner，S.，Chourasia，M.，Sicalo，J.，艾哈迈德，S。IL-1在IL-1诱导的炎症反应中的关键作用：与NF-Bp 65在转录调控中的合作。
The IL-1 cytokines are considered among the first family of cytokines that orchestrate acute and chronic inflammatory diseases. Both IL-1 and IL-1 are members of the IL-1 family; however, their distinct roles in the inflammatory processes remain poorly understood. We explored the role of IL-1 in IL-1-activated signaling pathways causing synovial inflammation in rheumatoid arthritis (RA). Using synovial fibroblasts isolated from RA joints, we found that IL-1 significantly stimulated IL-1 expression, which was selectively inhibited by blocking the NF-B pathway. Knockdown of IL-1 using small interfering RNA abolished IL-1-induced pro-IL-1 and pro-IL-1 expression and suppressed inflammation. Native and chromatin immunoprecipitation studies showed that IL-1 cooperates in NF-Bp65 binding to the distal region of IL-1 promoter and to the proximal region of IL-1 promoter upstream of the transcription start site to stabilize their gene transcription. Molecular dynamics simulation of IL-1 or IL-1 binding to IL-1 receptor showed distinct interaction sites that corroborate with the ability of IL-1 to differentially activate phosphorylation of signaling proteins compared with IL-1. Our study highlights the importance of IL-1 in mediating IL-1-induced inflammation in addition to maintaining its expression and providing a rationale for targeting IL-1 to minimize the role of IL-1 in inflammatory diseases like RA.Singh, A. K., Fechtner, S., Chourasia, M., Sicalo, J., Ahmed, S. Critical role of IL-1 in IL-1-induced inflammatory responses: cooperation with NF-Bp65 in transcriptional regulation.