Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes.
Long noncoding RNA LINC00305 promotes inflammation by activating the AHRR-NF-κB pathway in human monocytes.
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长非编码 RNA LINC00305 通过激活人单核细胞中的 AHRR-NF-kappa B 通路促进炎症
DOI：
10.1038/srep46204
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发表时间：
2017-04-10
影响因子：
4.6
通讯作者：
Liu DP
中科院分区：
文献类型：
--
作者：
Zhang DD;Wang WT;Xiong J;Xie XM;Cui SS;Zhao ZG;Li MJ;Zhang ZQ;Hao DL;Zhao X;Li YJ;Wang J;Chen HZ;Lv X;Liu DP
从全基因组关联研究（GWAS）积累的数据提供了一个新的候选基因的集合与复杂的疾病，如动脉粥样硬化。通过检索GWAS数据库，我们发现了一个位于长链非编码RNA（lncRNA）LINC 00305内含子中的与动脉粥样硬化相关的单核苷酸多态性（SNP）。尽管LINC 00305的功能尚不清楚，但我们发现LINC 00305在动脉粥样硬化斑块和单核细胞中表达丰富。LINC 00305的过表达促进了THP-1细胞中炎症相关基因的表达，并降低了共培养的人主动脉平滑肌细胞（HASMCs）中收缩标志物的表达。我们发现，LINC 00305的过表达激活了核因子-κ β（NF-κB），而NF-κB的抑制消除了LINC 00305介导的细胞因子表达的激活。在机制上，LINC 00305与脂质运载蛋白-1相互作用膜受体（LIMR）相互作用，增强LIMR与芳香烃受体阻遏物（AHRR）的相互作用，并促进AHRR的蛋白表达和核定位。此外，LINC 00305仅在LMR和AHRR存在下激活NF-κB。根据这些发现，我们提出LINC 00305通过促进LMR和AHRR的合作以及AHRR的激活来促进单核细胞炎症，其最终激活NF-κB，从而诱导HASMC表型转换。
Accumulating data from genome-wide association studies (GWAS) have provided a collection of novel candidate genes associated with complex diseases, such as atherosclerosis. We identified an atherosclerosis-associated single-nucleotide polymorphism (SNP) located in the intron of the long noncoding RNA (lncRNA) LINC00305 by searching the GWAS database. Although the function of LINC00305 is unknown, we found that LINC00305 expression is enriched in atherosclerotic plaques and monocytes. Overexpression of LINC00305 promoted the expression of inflammation-associated genes in THP-1 cells and reduced the expression of contractile markers in co-cultured human aortic smooth muscle cells (HASMCs). We showed that overexpression of LINC00305 activated nuclear factor-kappa beta (NF-κB) and that inhibition of NF-κB abolished LINC00305-mediated activation of cytokine expression. Mechanistically, LINC00305 interacted with lipocalin-1 interacting membrane receptor (LIMR), enhanced the interaction of LIMR and aryl-hydrocarbon receptor repressor (AHRR), and promoted protein expression as well as nuclear localization of AHRR. Moreover, LINC00305 activated NF-κB exclusively in the presence of LIMR and AHRR. In light of these findings, we propose that LINC00305 promotes monocyte inflammation by facilitating LIMR and AHRR cooperation and the AHRR activation, which eventually activates NF-κB, thereby inducing HASMC phenotype switching.