Mycophenolate Mofetil Protects Septic Mice via the Dual Inhibition of Inflammatory Cytokines and PD-1
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ORIGINAL ARTICLE
Mycophenolate Mofetil Protects Septic Mice via the Dual Inhibition of Inflammatory Cytokines and PD-1 Shun-wei Huang,1 Hao Chen,2 Mei-ling Lu,1 Jin-long Wang,1 Rong-li Xie,2 Bing Zhao,1 Ying Chen,1 Zhi-wei Xu,2 Jian Fei,2 En-qiang Mao,1 and Er-zhen Chen 1,3
Due to the imbalance between hyper-inflammation and hypo-inflammation, which are characterized by excessive cytokine productions and programmed death 1 (PD-1) upregulation, respectively, sepsis remains a highly lethal inflammatory syndrome with limited effective therapies. Mycophenolate mofetil (MMF), an immunosuppressant, has been reported to attenuate various inflammatory diseases. However, the role of MMF in sepsis therapy remains to be elucidated. C57BL-6J mice underwent cecal ligation and puncture (CLP) and were treated either with or without MMF. Survival rate and organ injuries were compared. Cytokine levels, bacteria clearance, apoptosis of spleen and peritoneal macrophages, and PD1 expression were assessed. At the beginning of CLP, 60 mg/kg MMF administered by gavage significantly protected septic mice, which was evidenced by improved survival and attenuated organ injuries, decreased cytokines, lower bacterial loads, and alleviated immune cell apoptosis. In addition, immune cells in the MMF mice showed lower PD-1 expression and improved immune response to pathogeny stimuli. MMF protects septic mice via the dual inhibition of cytokine releasing and PD-1 expression.
Abstract—
KEY WORDS: sepsis; mycophenolate mofetil; cytokine; programmed death 1.
INTRODUCTION Sepsis results in more than 10 million deaths annually, leading to high economic burdens globally [1, 2]. At present, however, no specific or effective anti-sepsis therapies except antibiotics are available to improve patient survival [3]. Sepsis begins with an overwhelming production of inflammatory mediators including interleukin 1β(IL-1β), Shun-wei Huang and Hao Chen contributed equally to this work. 1
Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China 2 Department of Surgery, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China 3 To whom correspondence should be addressed at Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, China. E-mail: [email protected]
IL-6, and tumor necrosis factor α(TNF-α) that results in tissue injuries and multiple organ failure, and is directly associated with mortality [4–7]. Alternatively, sepsis induces immune suppression that is characterized by lymphocyte exhaustion and the host’s inability to eradicate invading pathogens [8, 9]. Therefore, an appropriate therapy is one that suppresses the overwhelming inflammatory response while preserving the capability for pathogen clearance [10]. Mycophenolate mofetil (MMF) is an immunosuppressant which is extensively used to prevent rejection after organ transplantation [11]. As sepsis and other inflammato
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