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* Joint Immunology Laboratory of Institute of Health Sciences and Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, and Shanghai Institutes for Biological Sciences, Shanghai, China;
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China; and
E-Institutes of Shanghai Universities, Shanghai, China
Ethyl 2-[4-(12-
-artemisininoxy)]phenoxylpropionate (SM933) is a novel derivative of artemisinin, an herbal compound approved for the treatment of malaria. In this study, we show that SM933 has unique anti-inflammatory properties through regulation of signaling pathways, leading to amelioration of experimental autoimmune encephalomyelitis. The anti-inflammatory properties of SM933 were characterized by inhibition of encephalitogenic T cell responses that were altered to exhibit a Th2 immune deviation and reduced activity and concentration of NO and inducible NO synthase. The observed effect of SM933 was mediated through regulatory mechanisms involving the NF
B and the Rig-G/JAB1 signaling pathways. SM933 was found to inhibit the activity of NFB by up-regulating IB, which accounted for various down-stream anti-inflammatory actions. Furthermore, it up-regulated Rig-G through the action of IFN-
and prevented JAB1, a master cell cycle regulator, from entering the nucleus to promote p27 degradation, resulting in down-regulation of CDK2 and cyclin A and cell cycle progression. Regulation of the Rig-G/JAB1 pathway by SM933 led to altered cell cycle activity of encephalitogenic T cells as a result of its selective effect on activated, but not resting, T cells. The study indicates that SM933 is a novel anti-inflammatory agent acting through defined signaling mechanisms and provides regulatory mechanisms required for effective drug targeting in treatment of autoimmune disease and inflammation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Ministry of Science and Technology of China (2006CB943900), Chinese Academy of Sciences (KSCX1-YW-R-44), National Natural Science Foundation of China (NSF-30430650 and NSF-30571731), Shanghai Commission of Science and Technology (Grants 20014319207, 03DJ14009, 03XD14015, 04DZ19202, 04JC14040, and 04DZ14902), Specialized Research Fund for the Doctoral Program of Higher Education (SRFDP-20050266005), and Shanghai Leading Academic Discipline Project (T0206).
2 Z.W. and J.Q. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Jingwu Zhang, Institute of Health Sciences, 225 South Chongqing Road, Shanghai, China. E-mail address: jwzang{at}sibs.ac.cn
4 Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; iNOS, inducible NO synthase.
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