Novel sinomenine derivative 1032 improves immune suppression in experimental autoimmune encephalomyelitis.
Sinomenine (SIN) is an alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating autoimmune diseases. Due to its poor efficiency, the large-dose treatment presents some side effects and limits its further applications. In this study, we used chemical modification to improve the therapeutic effect of SIN in vitro and in vivo. A new derivative of sinomenine, named 1032, demonstrates significantly improved immunosuppressive activity over that of its parent natural compound (SIN). In an experimental autoimmune encephalomyelitis (EAE) model, 1032 significantly reduced encephalitogenic T cell responses and induced amelioration of EAE, which outcome was related to its selective inhibitory effect on the production of IL-17. By contrast, SIN treatment only led to a moderate alleviation of EAE severity and the expression level of IL-17 was not significantly reduced. Furthermore, 1032 exhibited suppression of Th17, but not Treg, cell differentiation, a result probably related to its inhibitory effect on IkappaB-alpha degradation as well as on IL-6 and TNF-alpha secretion in BMDCs. We speculate that 1032 as a novel anti-inflammatory agent may target DC to block IL-6 production, which in turn would terminate Th17 cell development. Thus, SIN derivative 1032 presents considerable potential in new drug development for treating autoimmune and inflammatory disease.
Yan
Ling-Chen
LC
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
Bi
En-Guang
EG
Lou
Yang-Tong
YT
Wu
Xiao-Dong
XD
Liu
Zhi-Duo
ZD
Zou
Jia
J
Zhou
Jia
J
Wang
Yuan
Y
Ma
Zhao
Z
Lin
Guo-Mei
GM
Sun
Shu-Hui
SH
Bian
Chao
C
Chen
Ai-Zhong
AZ
Yao
Zhu-Jun
ZJ
Sun
Bing
B
D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D020672:I-kappa B Proteins / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D020381:Interleukin-17 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009019:Morphinans / Q000737:chemistry / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology
C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D015850:Interleukin-6; D009019:Morphinans; C009271:sinomenine