Cyclin-Dependent Kinase 9 Inhibition Suppresses Necroptosis and Pyroptosis in the Progress of Endotoxemia
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ORIGINAL ARTICLE
Cyclin-Dependent Kinase 9 Inhibition Suppresses Necroptosis and Pyroptosis in the Progress of Endotoxemia Jiao Li,1,2 Huimin Mao,2 Yue Pan,2 Houxuan Li,3 and Lang Lei
1,4
Abstract— The host innate immune response stands at the first line of defense against the o-
utburst 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. KEY WORDS: cyclin-dependent kinase 9; endotoxemia; cell death; inflammation.
INTRODUCTION Endotoxemia, a life-threatening malady caused by excessive host responses to infection, is a systemic inflammatory disorder resulting from infection of invading 1
Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China 2 Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China 3 Department of Periodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China 4 To whom correspondence should be addressed at Department of Orthodontics, Nanjing Stomatological Hospital, Medical School of Nanjing University, Nanjing, China. E-mail: [email protected]
microorganisms. Endotoxemia may occur after surgery or trauma due to massive cell and tissue death, along with immune dysfunction. With a fatal outcome, it represents the leading cause of mortality worldwide [1]. Host-pathogen interactions may lead to survival or death of host cells depending on the clue from the environment [2]. Despite the widespread use of the apoptosisversus-necrosis paradigm, there is an increasing awareness of the complexity of processes occurring in dying cells that leads to the onset of death [3]. Several programmed cell deaths have been implicated in the interaction of host cells with pathogens, such as pyroptosis and necroptosis. Pyroptosis is a highly inflammatory form of regulated cell death
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