Department of Anatomy, Faculty of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Brain Res. 2009 Dec 22;1304:38-48. doi: 10.1016/j.brainres.2009.09.009. Epub 2009 Sep 10.
Interleukin-15 (IL-15) signaling has pleiotropic actions in many cell types during development and has been best studied in cells of immune system lineage, where IL-15 stimulates proliferation of cytotoxic T cells and induces maturation of natural killer cells. A few reports have indicated that IL-15 and the IL-15 receptor are expressed in central nervous system tissues and neuronal cell lines. Because this aspect of IL-15 action is poorly studied, we used cultured rat neural stem cells (NSCs) to study IL-15 signal transduction and activity. Primary cultures of rat NSCs in culture will form neurospheres and will differentiate into neuron, astrocyte, and oligodendrocyte progenitors under permissive conditions. We found by immunofluorescence that the IL-15Ralpha subunit of the IL-15 receptor was expressed in NSCs and differentiating neurons, but not astrocyte or oligodendrocyte progenitors. We also showed that IL-15 treatment reduced MAP-2 protein levels in neurons and could reduce neurite outgrowth in differentiating neurons but did not affect NSC proliferation, and cell proportions and viability of the corresponding lineage cells. In the presence of a STAT3 inhibitor, Stattic, IL-15 no longer reduced MAP-2 protein levels. IL-15 treatment caused STAT3 phosphorylation. Furthermore, using anti-IL-15Ralpha antibody to block IL-15 signaling completely inhibited IL-15-induced phosphorylation of STAT3 and prevented IL-15 from decreasing neurite outgrowth. In conclusion, IL-15 may influence neural cell differentiation through a signal transduction pathway involving IL-15Ralpha and STAT3. This signal transduction modifies MAP-2 protein levels and, consequently, the differentiation of neurons from NSCs, as evidenced by reduced neurite outgrowth.
白细胞介素-15 (IL-15) 信号在许多细胞类型的发育过程中具有多效性作用，并且在免疫系统谱系的细胞中得到了最好的研究，在这些细胞中，IL-15 刺激细胞毒性 T 细胞的增殖并诱导自然杀伤细胞的成熟。一些报道表明，IL-15 和 IL-15 受体在中枢神经系统组织和神经元细胞系中表达。由于 IL-15 作用的这一方面研究甚少，我们使用培养的大鼠神经干细胞 (NSC) 来研究 IL-15 信号转导和活性。在允许的条件下，原代培养的大鼠 NSCs 在培养中会形成神经球，并分化为神经元、星形胶质细胞和少突胶质细胞前体。我们通过免疫荧光发现，IL-15 受体的 IL-15Ralpha 亚基在 NSCs 和分化神经元中表达，但在星形胶质细胞或少突胶质细胞前体中不表达。我们还表明，IL-15 处理降低了神经元中的 MAP-2 蛋白水平，并可能减少分化神经元中的突起生长，但不影响 NSC 增殖以及相应谱系细胞的细胞比例和活力。在存在 STAT3 抑制剂 Stattic 的情况下，IL-15 不再降低 MAP-2 蛋白水平。IL-15 处理导致 STAT3 磷酸化。此外，使用抗 IL-15Ralpha 抗体完全阻断 IL-15 信号会抑制 IL-15 诱导的 STAT3 磷酸化，并阻止 IL-15 降低突起生长。总之，IL-15 可能通过涉及 IL-15Ralpha 和 STAT3 的信号转导途径影响神经细胞分化。这种信号转导改变了 MAP-2 蛋白水平，从而改变了 NSCs 中神经元的分化，如突起生长减少所证明的那样。
