Transcription modulation by CDK9 regulates inflammatory genes and RIPK3-MLKL-mediated necroptosis in periodontitis progression
Transcription modulation by CDK9 regulates inflammatory genes and RIPK3-MLKL-mediated necroptosis in periodontitis progression
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DOI：
10.1038/s41598-019-53910-y
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发表时间：
2019-11-22
影响因子：
4.6
通讯作者：
Lei, Lang
中科院分区：
文献类型：
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作者：
Li, Jiao;Shi, Jiahong;Lei, Lang
细胞周期蛋白依赖性激酶9（Cyclin-dependent kinase 9，CDK 9）是细胞存活和死亡的重要调节因子，是促进转录从暂停到延长的关键分子。然而，CDK 9在细菌性炎症性疾病中的病理功能从未被探索过。CDK 9抑制或敲低减弱牙龈卟啉单胞菌触发的炎性基因表达。单核细胞基因表达谱芯片分析显示，CDK 9的敲低不仅影响炎症反应，而且影响细胞死亡网络，特别是牙龈卟啉单胞菌感染后受体相互作用蛋白激酶3（RIPK 3）-混合谱系激酶结构域样（MLKL）介导的坏死性凋亡。抑制CDK 9显著降低坏死性凋亡，同时下调MLKL和磷酸化MLKL。通过调节caspase-8和细胞FLICE抑制蛋白（cFLIP），调节细胞存活和死亡的关键分子，CDK 9不仅影响经典的RIPK 1-RIPK 3介导的坏死性凋亡，而且还影响含有接头的替代TIR结构域诱导干扰素β-RIPK 3介导的坏死性凋亡。在体内皮下腔室模型中，CDK 9抑制抑制了急性感染过程中的促炎基因产生。此外，CDK 9抑制有助于减少牙周骨丢失和牙龈卟啉单胞菌在牙周微环境中诱导的炎症反应。总之，通过调节RIPK 3-MLKL介导的坏死性凋亡，CDK 9抑制提供了影响牙周环境中细菌感染进展的新机制。
Cyclin-dependent kinase 9 (CDK9), one crucial molecule in promoting the transition from transcription pausing to elongation, is a critical modulator of cell survival and death. However, the pathological function of CDK9 in bacterial inflammatory diseases has never been explored. CDK9 inhibition or knock-down attenuated Porphyromonas gingivalis-triggered inflammatory gene expression. Gene-expression microarray analysis of monocytes revealed that knock-down of CDK9 not only affected inflammatory responses, but also impacted cell death network, especially the receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase domain-like (MLKL)-mediated necroptosis after P. gingivalis infection. Inhibition of CDK9 significantly decreased necroptosis with downregulation of both MLKL and phosphorylated MLKL. By regulating caspase-8 and cellular FLICE inhibitory protein (cFLIP), key molecules in regulating cell survival and death, CDK9 affected not only the classic RIPK1-RIPK3-mediated necroptosis, but also the alternate TIR-domain-containing adapter-inducing interferon-beta-RIPK3-mediated necroptosis. CDK9 inhibition dampened pro-inflammatory gene production in the acute infection process in the subcutaneous chamber model in vivo. Moreover, CDK9 inhibition contributed to the decreased periodontal bone loss and inflammatory response induced by P. gingivalis in the periodontal micro-environment. In conclusion, by modulating the RIPK3-MLKL-mediated necroptosis, CDK9 inhibition provided a novel mechanism to impact the progress of bacterial infection in the periodontal milieu.