Damage associated molecular pattern molecule-induced microRNAs (DAMPmiRs) in human peripheral blood mononuclear cells.
Damage associated molecular pattern molecule-induced microRNAs (DAMPmiRs) in human peripheral blood mononuclear cells.
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DOI：
10.1371/journal.pone.0038899
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lotze MT
中科院分区：
文献类型：
--
作者：
Unlu S;Tang S;Wang E;Martinez I;Tang D;Bianchi ME;Zeh HJ 3rd;Lotze MT
从坏死、受损或应激细胞释放的内源性损伤相关分子模式分子（DAMP）与炎症反应相关。这种反应的microRNA（miR）表达特征是否与病原体相关分子模式（PAMP）刺激的炎症反应不同尚不清楚。我们在此报告，miR-34 c和miR-214在暴露于含DAMP的冻融裂解物或来自血清饥饿和葡萄糖剥夺细胞的条件培养基的新鲜人外周血单核细胞（PBMC）中显著表达（p<6×10−4和p<3.7×10−3）。有趣的是，与暴露于来自HMGB 1 −/− MEF的裂解物或条件培养基的培养物相比，暴露于来自野生型高迁移率族B1（HMGB 1 +/+）小鼠胚胎成纤维细胞（MEF）的冻融裂解物或条件培养基的PBMC中仅miR-34 c表达差异。miR-155在这些培养物中的表达可忽略不计，但在用脂多糖（LPS）或大多数其他Toll样受体（TLR）配体刺激的PBMC中显著表达，使其成为原型“PAMPmiR”。暴露于受损的人结肠直肠癌细胞系裂解物（HCT 116）类似地导致miR-34 c和miR-214水平增加。当PBMC用抗miR-34 c预转染，然后暴露于裂解物时，IKKγ mRNA（miR-34 c的假定靶点）的表达水平增加，而用pre-miR-34 c转染的培养物中IKKγ的蛋白水平被废除。当PBMC培养物与K+通道（炎性体）抑制剂格列本脲短暂预孵育时，miR-34 c表达水平（以及促炎细胞因子IL-1β和TNFα）降低，表明炎性体激活是miR-34 c表达的上游，对DAMP产生应答。我们的研究结果表明，特定的microRNA表达特征与受损/损伤细胞的炎症反应相关，并对许多急性和慢性炎症性疾病产生影响。
Endogenous damage associated molecular pattern molecules (DAMPs) released from necrotic, damaged or stressed cells are associated with an inflammatory response. Whether the microRNA (miR) expression signature of this response is different from that of a pathogen associated molecular pattern (PAMP)-stimulated inflammatory response is unknown. We report here that miR-34c and miR-214 are significantly expressed in fresh human peripheral blood mononuclear cells (PBMCs) exposed to DAMP-containing freeze-thaw lysates, or to conditioned media from serum-starved and glucose-deprived cells (p<6×10−4 and p<3.7×10−3), respectively. Interestingly, only miR-34c expression was differentially expressed in PBMCs exposed to freeze-thaw lysates or conditioned media from wildtype High Mobility Group B1 (HMGB1+/+) mouse embryonic fibroblast (MEF) cells, when compared to cultures exposed to lysates or conditioned media from HMGB1−/− MEFs. miR-155 expression in these cultures was negligible, but was significantly expressed in PBMCs stimulated with Lipopolysaccahride (LPS) or most other Toll-like receptor (TLR) ligands, making it the prototypic “PAMPmiR”. Exposure to a damaged human colorectal carcinoma cell line lysate (HCT116) similarly resulted in increased miR-34c and miR-214 levels. When PBMCs were pre-transfected with anti-miR-34c and then exposed to lysate, expression levels of IKKγ mRNA, a putative target of miR-34c, increased, while protein levels of IKKγ in cultures transfected with a pre-miR-34c were abrogated. Levels of miR-34c expression (as well as pro-inflammatory cytokines, IL-1β and TNFα) decreased when PBMC cultures were briefly pre-incubated with the K+ channel (inflammasome) inhibitor, glybenclamide, suggesting that inflammasome activation is upstream of miR-34c expression in response to DAMPs. Our findings demonstrate that a specific microRNA expression signature is associated with the inflammatory response to damaged/injured cells and carries implications for many acute and chronic inflammatory disorders.
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