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Mycophenolate Mofetil Protects Septic Mice via the Dual Inhibition of Inflammatory Cytokines and PD-1

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Abstract

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 PD-1 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.

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Funding

The work is supported by the National Natural Science Foundation of China (No. 81571931 to Er-zhen Chen, No. 81671901 to En-qiang Mao, No. 8167030165 to Jian Fei, and No. 81600501 to Ying Chen) and Shanghai Municipal Planning Commission of Science and Research Fund (No. 2016ZB0206 to Er-Zhen Chen).

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  1. Shun-wei Huang and Hao Chen contributed equally to this work.

Authors and Affiliations

  1. Department of Emergency, Rui** Hospital, Shanghai Jiao Tong University, School of Medicine, 197 Rui** Er Road, Shanghai, 200025, China

    Shun-wei Huang, Mei-ling Lu, **-long Wang, Bing Zhao, Ying Chen, En-qiang Mao & Er-zhen Chen

  2. Department of Surgery, Rui** Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    Hao Chen, Rong-li **e, Zhi-wei Xu & Jian Fei

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  1. Shun-wei Huang
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  2. Hao Chen
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  5. Rong-li **e
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  6. Bing Zhao
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  7. Ying Chen
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  10. En-qiang Mao
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  11. Er-zhen Chen
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Correspondence to Er-zhen Chen.

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The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

Animal studies were approved by the Animal Ethics Committee of Rui** Hospital affiliated with Shanghai Jiao Tong University, School of Medicine (No. 092), and were in strict agreement with the international guidelines for care and use of laboratory animals.

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Huang, Sw., Chen, H., Lu, Ml. et al. Mycophenolate Mofetil Protects Septic Mice via the Dual Inhibition of Inflammatory Cytokines and PD-1. Inflammation 41, 1008–1020 (2018). https://doi.org/10.1007/s10753-018-0754-2

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