Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, PR China.
Modern Research Center for Traditional Chinese Medicine, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, PR China.
Int Immunopharmacol. 2019 Feb;67:473-482. doi: 10.1016/j.intimp.2018.12.048. Epub 2018 Dec 28.
Activated B cells targeted to autoantigens proliferate and differentiate into antibody-secreting cells. Overproduced autoantibodies will give rise to autoimmune diseases. In this study, we investigated the inhibitory effects of GYF-21, an epoxide 2‑(2‑phenethyl)‑chromone derivative extracted from Chinese agarwood, on the survival, activation, proliferation, and differentiation of B cells for revealing its potential to treat autoimmune diseases related to B cell dysfunction. The results showed that GYF-21 slightly inhibited the survival, activation and proliferation of B cells stimulated by combination of anti-IgM, anti-CD40 and IL-4 while weakly up-regulated differentiation of B cells induced by combination of anti-CD40 and IL-4. In addition, GYF-21 intensively suppressed survival, activation, proliferation, and differentiation of B cells stimulated by B-cell activating factor (BAFF) which plays extremely important roles in autoantibody production and pathogenesis of autoimmune diseases. The mechanism study revealed that GYF-21 slightly down-regulated phosphorylation of NF-κB p65, Akt, STAT3, but up-regulated phosphorylation of Erk1/2 in B cells activated by anti-IgM, anti-CD40, IL-4 or their combinations. However, GYF-21 not only moderately down-regulated phosphorylation of NF-κB p65 and MAPK p38, but also intensively inhibited phosphorylation of Erk1/2 and Akt induced by BAFF. These data suggest the inhibitory effects of GYF-21 on the survival, activation, proliferation, and differentiation of B cells mainly via blocking BAFF activated signaling pathways, and its potential to be developed into therapeutic drug for autoimmune diseases, especially systemic lupus erythematosus (SLE).
活化的针对自身抗原的 B 细胞增殖并分化为分泌抗体的细胞。过量产生的自身抗体将导致自身免疫性疾病。在这项研究中，我们研究了 GYF-21（一种从中国沉香中提取的环氧 2-（2-苯乙基）-色酮衍生物）对 B 细胞存活、活化、增殖和分化的抑制作用，以揭示其治疗与 B 细胞功能障碍相关的自身免疫性疾病的潜力。结果表明，GYF-21 轻度抑制了由抗 IgM、抗 CD40 和 IL-4 联合刺激的 B 细胞的存活、活化和增殖，而弱上调了由抗 CD40 和 IL-4 联合诱导的 B 细胞的分化。此外，GYF-21 强烈抑制了 B 细胞激活因子（BAFF）刺激的 B 细胞的存活、活化、增殖和分化，BAFF 在自身抗体产生和自身免疫性疾病发病机制中起着至关重要的作用。机制研究表明，GYF-21 轻度下调了由抗 IgM、抗 CD40、IL-4 或其组合激活的 B 细胞中 NF-κB p65、Akt、STAT3 的磷酸化，但上调了 Erk1/2 的磷酸化。然而，GYF-21 不仅中度下调了 NF-κB p65 和 MAPK p38 的磷酸化，而且强烈抑制了由 BAFF 诱导的 Erk1/2 和 Akt 的磷酸化。这些数据表明，GYF-21 对 B 细胞的存活、活化、增殖和分化的抑制作用主要通过阻断 BAFF 激活的信号通路，其具有开发为治疗自身免疫性疾病，特别是系统性红斑狼疮（SLE）的治疗药物的潜力。
