Département de Pharmacologie, Université de Montréal, Montreal, Canada.
J Immunol. 2009 Dec 15;183(12):7692-702. doi: 10.4049/jimmunol.0901464.
IL-27 is formed by the association of a cytokine subunit, p28, with the soluble cytokine receptor EBV-induced gene 3 (EBI3). The IL-27R comprises gp130 and WSX-1. The marked difference between EBI3(-/-) and WSX-1(-/-) mice suggests that p28 has functions independent of EBI3. We have identified an alternative secreted complex formed by p28 and the soluble cytokine receptor cytokine-like factor 1 (CLF). Like IL-27, p28/CLF is produced by dendritic cells and is biologically active on human NK cells, increasing IL-12- and IL-2-induced IFN-gamma production and activation marker expression. Experiments with Ba/F3 transfectants indicate that p28/CLF activates cells expressing IL-6Ralpha in addition to the IL-27R subunits. When tested on CD4 and CD8 T cells, p28/CLF induces IL-6Ralpha-dependent STAT1 and STAT3 phosphorylation. Furthermore, p28/CLF inhibits CD4 T cell proliferation and induces IL-17 and IL-10 secretion. These results indicate that p28/CLF may participate in the regulation of NK and T cell functions by dendritic cells. The p28/CLF complex engages IL-6R and may therefore be useful for therapeutic applications targeting cells expressing this receptor. Blocking IL-6R using humanized mAbs such as tocilizumab has been shown to be beneficial in pathologies like rheumatoid arthritis and juvenile idiopathic arthritis. The identification of a new IL-6R ligand is therefore important for a complete understanding of the mechanism of action of this emerging class of immunosuppressors.
IL-27 由细胞因子亚单位 p28 与可溶性细胞因子受体 EBV 诱导基因 3（EBI3）组成。IL-27R 由 gp130 和 WSX-1 组成。EBI3(-/-) 和 WSX-1(-/-) 小鼠之间的显著差异表明 p28 具有独立于 EBI3 的功能。我们已经鉴定出另一种由 p28 和可溶性细胞因子受体细胞因子样因子 1（CLF）组成的分泌复合物。与 IL-27 一样，p28/CLF 由树突状细胞产生，对人类 NK 细胞具有生物活性，增加 IL-12 和 IL-2 诱导的 IFN-γ产生和激活标志物表达。用 Ba/F3 转染子进行的实验表明，p28/CLF 激活表达 IL-6Ralpha 的细胞，除了 IL-27R 亚基之外。在 CD4 和 CD8 T 细胞上进行测试时，p28/CLF 诱导 IL-6Ralpha 依赖性 STAT1 和 STAT3 磷酸化。此外，p28/CLF 抑制 CD4 T 细胞增殖并诱导 IL-17 和 IL-10 分泌。这些结果表明，p28/CLF 可能通过树突状细胞参与 NK 和 T 细胞功能的调节。p28/CLF 复合物结合 IL-6R，因此可能对靶向表达这种受体的细胞的治疗应用有用。使用针对 IL-6R 的人源化 mAbs（如托珠单抗）阻断 IL-6R 已被证明对类风湿关节炎和幼年特发性关节炎等病理学有益。因此，鉴定一种新的 IL-6R 配体对于全面了解这一新兴免疫抑制剂类别的作用机制非常重要。
