@article{APS7934,
author = {Fang-yuan Kong and Wei Chen and Shi-jun He and Ze-min Lin and Xin Li and Xiao-hui Zhang and Xiao-qian Yang and Feng-hua Zhu and Xian-kun Tong and Yu Zhou and Wei Tang and Wen-hu Duan and Jian-ping Zuo},
title = {Mycophenolic acid derivative 118 improves outcome of skin grafts by suppressing IL-17 production},
journal = {Acta Pharmacologica Sinica},
volume = {34},
number = {7},
year = {2016},
keywords = {},
abstract = {Fang-yuan KONG1, #, Wei CHEN1, #, Shi-jun HE1, Ze-min LIN1, Xin LI1, Xiao-hui ZHANG1, Xiao-qian YANG1, Feng-hua ZHU1, Xian-kun TONG1, Yu ZHOU1, Wei TANG1, *, Wen-hu DUAN1, *, Jian-ping ZUO1, 2, *
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; 2Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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.
Keywords: mycophenolate mofetil; derivative 118; transplantation; skin graft; allograft; syngraft; IL-17; IL-23
This work was supported by grants from the National Natural Science Foundation of China (NSFC)(Nos 81072652, 81273524, and 81273525).
# These authors contributed equally to this work.
* To whom correspondence should be addressed.
E-mail jpzuo@mail.shcnc.ac.cn (Jian-ping ZUO); whduan@mail.shcnc.ac.cn (Wen-hu DUAN);
xwhduan@mail.shcnc.ac.cn (Wei TANG)
Received 2012-11-13 Accepted 2013-02-07},
issn = {1745-7254}, url = {http://www.chinaphar.com/article/view/7934}
}