Graduate Institute of Life Sciences, National Defense Medical Center, Neihu, Taipei 114, Taiwan.
J Autoimmun. 2011 Nov;37(3):160-70. doi: 10.1016/j.jaut.2011.05.013. Epub 2011 Jul 1.
The pre-ligand assembly domain (PLAD) of tumor necrosis factor receptors mediates specific ligand-independent receptor assembly and subsequent signaling. However, the physiological role of PLAD in the regulation of TNFR-mediated immune responses in autoimmunity is still unclear. By using the recombinant PLAD.Fc protein to block TNFR1 assembly, we demonstrated that PLAD.Fc treatment significantly reduced the TNFR1-driving proinflammatory cytokines and protected NOD mice from diabetes. Strikingly, Th17 differentiation was significantly inhibited in PLAD.Fc-treated NOD and TNFR1-deficient mice, indicating a TNFR1-dependent Th17 development. PLAD.Fc-modulated effects on DCs, in terms of the downregulation of Th17-inducing cytokines, IL-6 and TGF-β, explained the potential mechanism for Th17 suppression. Finally, we provided an additional result that PLAD.Fc administration diminished the infiltration of Th17 cells in the central nervous system and ameliorated the experimental autoimmune encephalomyelitis in mice. Collectively, these data demonstrated that targeting PLAD of TNFR1 provides protection from autoimmune diseases through the downregulation of Th17 and suggested a therapeutic potential of PLAD-modulation in TNF-involved inflammatory diseases.
肿瘤坏死因子受体的预配体组装结构域（PLAD）介导特定的配体非依赖性受体组装及随后的信号转导。然而，PLAD 在调节自身免疫中的 TNFR 介导的免疫反应中的生理作用尚不清楚。通过使用重组 PLAD.Fc 蛋白阻断 TNFR1 组装，我们证明 PLAD.Fc 处理显著降低了 TNFR1 驱动的促炎细胞因子，并保护 NOD 小鼠免于糖尿病。引人注目的是，PLAD.Fc 处理的 NOD 和 TNFR1 缺陷型小鼠中的 Th17 分化明显受到抑制，表明 Th17 的发展依赖于 TNFR1。PLAD.Fc 对 DC 调节的作用，下调了 Th17 诱导细胞因子 IL-6 和 TGF-β，解释了抑制 Th17 的潜在机制。最后，我们提供了一个额外的结果，PLAD.Fc 给药减少了 Th17 细胞在中枢神经系统的浸润，并改善了实验性自身免疫性脑脊髓炎在小鼠中的发病。总之，这些数据表明，针对 TNFR1 的 PLAD 可通过下调 Th17 提供对自身免疫性疾病的保护，并提示 PLAD 调节在 TNF 参与的炎症性疾病中的治疗潜力。
