The host innate immune response stands at the first line of defense against the outburst of pathogen invasion and their byproduct release. The balanced and coordinated expression of genes in normal immune responses is compromised in the progress of endotoxemia with exacerbated inflammation and massive cell death. In the present study, we identified cyclin-dependent kinase 9 (CDK9), the functional subunit of the positive transcription elongation factor b, as a master regulator of inflammatory gene transcription in the process of promoter-proximal pausing to productive elongation. Therapeutic pharmacological inhibition of CDK9 by flavopiridol (FVD) rescued mice from death in experimental models of fatal endotoxemia. In addition to alleviation of the cytokine storm in the circulation system following lethal endotoxin injection, FVD treatment significantly dampened the onset of inflammation in the livers and lungs and reduced the necroptosis and pyroptosis in livers. Moreover, CDK9 inhibition reduced inflammatory cytokine release and decreased cell death in the pro-inflammatory pyroptotic and necroptotic cell death pathway in monocytes in responses to lipopolysaccharide. In conclusion, CDK9 inhibition may affect the progress of endotoxemia by dampening inflammation and cell death including necroptosis and pyroptosis.

宿主先天免疫反应是抵御病原体入侵及其副产物释放的第一道防线。在内毒素血症的进展中，正常免疫反应中基因的平衡和协调表达受到损害，炎症加剧和大量细胞死亡。在本研究中，我们确定了细胞周期蛋白依赖性激酶 9 (CDK9)，即正转录延伸因子 b 的功能亚基，作为启动子近端暂停到生产性延伸过程中炎症基因转录的主要调节因子。在致命性内毒素血症的实验模型中，黄酮吡醇 (FVD) 对 CDK9 的治疗性药理学抑制使小鼠免于死亡。除了缓解致命内毒素注射后循环系统中的细胞因子风暴，FVD 治疗显着抑制了肝脏和肺部炎症的发作，并减少了肝脏的坏死性凋亡和细胞焦亡。此外，CDK9 抑制减少了炎症细胞因子的释放，并减少了单核细胞响应脂多糖的促炎性焦亡和坏死性细胞死亡途径中的细胞死亡。总之，CDK9 抑制可能通过抑制炎症和细胞死亡（包括坏死性凋亡和细胞焦亡）来影响内毒素血症的进展。