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Novel Immunomodulatory Properties of Berbamine through Selective Down-Regulation of STAT4 and Action of IFN- in Experimental Autoimmune Encephalomyelitis¹

Yiping Ren^2,*, Limin Lu^2,*, Taylor B. Guo^*, Ju Qiu^*, Yiqing Yang^*, Ailian Liu^* and Jingwu Z. Zhang^3,*,

^* Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiaotong University School of Medicine, and E-Institutes of Shanghai Universities, Shanghai, China

Berbamine (BM) is an herbal compound derived from Berberis vulgaris L commonly used in traditional Chinese medicine. In this study, we show that BM has potent anti-inflammatory properties through novel regulatory mechanisms, leading to reduced encephalitogenic T cell responses and amelioration of experimental autoimmune encephalomyelitis (EAE). The treatment effect of BM was attributable to its selective inhibitory effect on the production and action of IFN- in CD4⁺ T cells, which was mediated through altered STAT4 expression in T cells. BM was found to up-regulate SLIM, a ubiquitin E3 ligase for STAT4, and promote STAT4 degradation, resulting in markedly decreased IFN- production in CD4⁺ T cells in EAE mice. Regulation of IFN- by BM had profound anti-inflammatory actions through its effect on both CD4⁺ T cells and APCs. BM-treated APCs exhibited reduced stimulatory function as a result of altered expression of PD-L1, CD80, and CD86 in treated mice. The treatment effect of BM in EAE was directly related to its action on IFN-, and was abolished in IFN- knockout mice. The study also confirmed that BM was able to inhibit NFAT translocation through effecting calcium mobilization in lymphocytes. However, this effect was not directly responsible for the treatment efficacy of BM in EAE. The study has important implications in our approaches to evaluating the utility of natural compounds in drug discovery and to probing the role of cytokine network in the development of autoimmune conditions.

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 the National Natural Science Foundation of China (NSF-30430650 and NSF-30571731), the Shanghai Commission of Science and Technology (20014319207, 03DJ14009, 03XD14015, 04DZ19202, 04JC14040, and 04DZ14902), and the Shanghai Leading Academic Discipline Project (T0206).

² Y.R. and L.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Jingwu Zhang, Institute of Health Sciences, 225 South Chongqing Road, Shanghai 200025, China. E-mail address: jwzang{at}sibs.ac.cn

⁴ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; BM, berbamine; GKO, IFN- knockout; MOG, myelin oligodendrocyte glycoprotein; [Ca²⁺]_i, intracellular calcium concentration.

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