Anti-inflammatory properties and regulatory mechanism of a novel derivative of artemisinin in experimental autoimmune encephalomyelitis.

Abstract

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.

• Authors: Zhaojun Wang, Ju Qiu, Taylor B Guo, Ailian Liu, Ying Wang, Yin Li, Jingwu Z Zhang
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 9 Pg. 5958-65 (Nov 01 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17947669 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Artemisinins
• Inflammation Mediators
• NF-kappa B
• ethyl 2-(4-(12-beta-artemisininoxy))phenoxylpropionate

Topics

• Animals
• Artemisinins (chemistry, metabolism, pharmacology)
• Cell Proliferation
• Cells, Cultured
• Encephalomyelitis, Autoimmune, Experimental (chemically induced, immunology, metabolism, pathology)
• Inflammation Mediators (metabolism)
• Lymphocyte Activation (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Structure
• NF-kappa B (metabolism)
• Spleen (drug effects, metabolism)
• T-Lymphocytes (cytology, drug effects, immunology)