Anti-inflammatory properties and regulatory mechanism of a novel derivative of artemisinin in experimental autoimmune encephalomyelitis.
Ethyl 2-[4-(12-beta-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 NFkappaB and the Rig-G/JAB1 signaling pathways. SM933 was found to inhibit the activity of NFkappaB by up-regulating IkappaB, which accounted for various down-stream anti-inflammatory actions. Furthermore, it up-regulated Rig-G through the action of IFN-alpha 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.
Wang
Zhaojun
Z
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.
Qiu
Ju
J
Guo
Taylor B
TB
Liu
Ailian
A
Wang
Ying
Y
Li
Yin
Y
Zhang
Jingwu Z
JZ
D000818:Animals; D037621:Artemisinins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D049109:Cell Proliferation; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D037621:Artemisinins; D018836:Inflammation Mediators; D016328:NF-kappa B; C524564:ethyl 2-(4-(12-beta-artemisininoxy))phenoxylpropionate