Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, ON, Canada M5G 2C1.
Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):21034-9. doi: 10.1073/pnas.1215558110. Epub 2012 Dec 3.
The endogenous metabolite of estradiol, 2-Methoxyestradiol (2ME2), is an antimitotic and antiangiogenic cancer drug candidate that also exhibits disease-modifying activity in animal models of rheumatoid arthritis (RA). We found that 2ME2 dramatically suppresses development of mouse experimental autoimmune encephalomyelitis (EAE), a rodent model of multiple sclerosis (MS). 2ME2 inhibits in vitro lymphocyte activation, cytokine production, and proliferation in a dose-dependent fashion. 2ME2 treatment of lymphocytes specifically reduced the nuclear translocation and transcriptional activity of nuclear factor of activated T-cells (NFAT) c1, whereas NF-κB and activator protein 1 (AP-1) activation were not adversely affected. We therefore propose that 2ME2 attenuates EAE through disruption of the NFAT pathway and subsequent lymphocyte activation. By extension, our findings provide a molecular rationale for the use of 2ME2 as a tolerable oral immunomodulatory agent for the treatment of autoimmune disorders such as MS in humans.
雌二醇的内源性代谢物 2-甲氧基雌二醇（2ME2）是一种抗有丝分裂和抗血管生成的癌症候选药物，在类风湿关节炎（RA）的动物模型中也表现出疾病修饰活性。我们发现 2ME2 可显著抑制实验性自身免疫性脑脊髓炎（EAE）的发生，EAE 是多发性硬化症（MS）的啮齿动物模型。2ME2 以剂量依赖性方式抑制体外淋巴细胞激活、细胞因子产生和增殖。2ME2 处理淋巴细胞特异性地减少了活化 T 细胞核因子（NFAT）c1 的核易位和转录活性，而 NF-κB 和激活蛋白 1（AP-1）的激活不受不利影响。因此，我们提出 2ME2 通过破坏 NFAT 途径和随后的淋巴细胞激活来减轻 EAE。因此，我们的发现为将 2ME2 用作治疗人类自身免疫性疾病（如 MS）的可耐受口服免疫调节剂提供了分子依据。
