一种新型青蒿素衍生物在实验性自身免疫性脑脊髓膜炎中的抗炎及免疫调节作用

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 (EAE). 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 iNOS. The observed effect of SM933 was mediated through regulatory mechanisms involving the NFκB and the Rig-G/JAB1 signaling pathways. SM933 was found to inhibit the activity of NFκB by up-regulating IκB, which accounted for various down-stream anti-inflammatory actions. Furthermore, it interacted Rig-G through the action of interferon-α and prevented JAB-1, a master cell cycle regulator, from entering into the nucleus where JAB-1 regulates P27 and its downstream molecules, Cyclin A and CDK2. Regulation of the Rig-G/JAB-1 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.