Original Article | Published:

Mycophenolic acid derivative 118 improves outcome of skin grafts by suppressing IL-17 production

Acta Pharmacologica Sinica volume 34, pages 921929 (2013) | Download Citation

Subjects

Abstract

Aim:

To investigate the effects and underlying mechanisms of 118, a novel derivative of mycophenolic acid, in a murine allogeneic skin graft model.

Methods:

Skin grafts were conducted by grafting BALB/c donor tail skin into C57BL/6 skin beds (allograft) or by grafting female C57BL/6 donor tail skin into female C57BL/6 skin beds (syngraft). The mice were treated with the derivative 118 (40 mg·kg−1·d−1, po) for 13 d (3 d before and 10 d after transplantation). Skin grafts, splenocytes and graft-infiltrated lymphocytes were isolated and examined ex vivo. The effects of the derivative 118 on naive CD4+ T cell differentiation were examined in vitro.

Results:

Treatment with the derivative 118 dramatically increased the survival rate of murine allogeneic skin grafts. Flow cytometric analysis and H&E staining showed that the derivative significantly decreased inflammatory cell infiltration into the grafts. The levels of the chemokines CXCL1, CXCL2, CCL7, and CCL2 were reduced in the derivative 118-treated grafts. Additionally, the derivative 118 significantly suppressed the IL-17 levels in the grafts but did not affect the differentiation of systemic helper T cells in the murine allogeneic skin graft model. Furthermore, IL-23p19 expression was suppressed in the grafts from the derivative 118-treated group, which might be due to decreases in TLR4 and MyD88 expression. Finally, the derivative 118 did not exert direct influences on helper T cell differentiation in vitro.

Conclusion:

Treatment with the mycophenolic acid derivative 118 improves murine allogeneic skin grafts by decreasing IL-23 expression and suppressing local IL-17 secretion in the grafts, rather than directly inhibiting Th17 differentiation.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (NSFC) (Nos 81072652, 81273524, and 81273525).

Author information

Author notes

    • Fang-yuan Kong
    •  & Wei Chen

    These authors contributed equally to this work.

Affiliations

  1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

    • Fang-yuan Kong
    • , Wei Chen
    • , Shi-jun He
    • , Ze-min Lin
    • , Xin Li
    • , Xiao-hui Zhang
    • , Xiao-qian Yang
    • , Feng-hua Zhu
    • , Xian-kun Tong
    • , Yu Zhou
    • , Wei Tang
    • , Wen-hu Duan
    •  & Jian-ping Zuo
  2. Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China

    • Jian-ping Zuo

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Correspondence to Wei Tang or Wen-hu Duan or Jian-ping Zuo.

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https://doi.org/10.1038/aps.2013.14

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