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Cyclin-Dependent Kinase 9 Inhibition Suppresses Necroptosis and Pyroptosis in the Progress of Endotoxemia

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Abstract

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.

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Funding

This work was supported by the National Natural Science Foundation of China (81400516), Natural Science Foundation of Jiangsu Province (No. BK20171122), and Nanjing Medical Science and Technique Development Foundation (QRX17081).

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Authors and Affiliations

  1. Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China

    Jiao Li & Lang Lei

  2. Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China

    Jiao Li, Huimin Mao & Yue Pan

  3. Department of Periodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China

    Houxuan Li

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  1. Jiao Li
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  2. Huimin Mao
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Contributions

Experiments, data collection, and analysis were performed by Jiao Li, Huimin Mao, and Yue Pan. The first draft of the manuscript was written by Jiao Li. Lang Lei and Houxuan Li designed the study and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Lang Lei.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (the Medical Ethics Committee of Nanjing Stomatological Hospital, Medical School of Nanjing University, 2017NL-012(KS)).

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Li, J., Mao, H., Pan, Y. et al. Cyclin-Dependent Kinase 9 Inhibition Suppresses Necroptosis and Pyroptosis in the Progress of Endotoxemia. Inflammation 43, 2061–2074 (2020). https://doi.org/10.1007/s10753-020-01274-1

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