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Regulatory Properties of Copolymer I in Th17 Differentiation by Altering STAT3 Phosphorylation¹

Chunhua Chen^*, Xuebin Liu, Bing Wan and Jingwu Z. Zhang^2,*

^* Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai JiaoTong University School of Medicine, Shanghai, China; and Department of Neuroinflammation, GlaxoSmithKline Research and Development Center, Shanghai, China

Th17 and Th1 play an important role in multiple sclerosis for which copolymer I (COP-I) is a treatment option. We described here that the treatment effect of COP-I correlated with its unique regulatory properties on differentiation and survival of Th17 in experimental autoimmune encephalomyelitis mice, which was mediated through down-regulation of STAT3 phosphorylation. The effect of COP-I on Th17 differentiation required CD14⁺ monocytes through IL-6 signaling as a key mediator to regulate STAT3 phosphorylation and subsequent RORt expression in Th17 cells. The observed effect was markedly dampened when monocytes were genetically deficient for IL-6. Similar regulatory properties of COP-I were demonstrated in human Th17 differentiation. The study revealed the differential regulatory roles and the novel mechanism of action of COP-I chiefly responsible for its treatment efficacy in experimental autoimmune encephalomyelitis and multiple sclerosis.

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 NSF-30430650 and NSF-30571731 from the National Natural Science Foundation of China and by Grant 04DZ14902 from the Shanghai Commission of Science and Technology.

² 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

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; COP-I, copolymer I; MS, multiple sclerosis; MOG, myelin oligodendrocyte glycoprotein; GKO, IFN- knockout; MBP, myelin basic protein; ROR, retinoic acid-related orphan receptor.