Anti-IL-6 activity of Notch signal : development of new therapeutic approaches for multiple myeloma

IL-6被广泛认为是通过旁分泌和自分泌机制刺激骨髓瘤细胞增殖的主要细胞因子。我们以前报道过IL-6抑制人血单核细胞向真皮树突状细胞的分化。骨髓瘤细胞产生的IL-6可能至少部分参与了多发性骨髓瘤患者的免疫缺陷。当我们开始这项研究时，我们的目标是通过抗IL-6信号恢复与多发性骨髓瘤相关的免疫缺陷。在研究过程中，我们偶然发现固定化Notch配体Delta-1在人血单核细胞分化为朗格汉斯细胞中起着至关重要的作用。最近，据报道，Notch配体Delta-1在皮肤的一定比例中表达。GM-CSF和TGF-β1也在皮肤中分泌。我们在此报道Notch配体Delta-1与GM-CSF和TGF-β1共同诱导人CD 14 ^+血单核细胞分化为CD 14 ^+细胞。 ...更多信息 表达朗格汉斯细胞标志物：CD 1a、Langerin、皮肤淋巴细胞相关抗原、CC趋化因子受体6和E-钙粘蛋白。透射电镜观察细胞表面有长而突出的树突，树突均匀分布于细胞表面，细胞内含有多个细胞器。杆状或球拍形的Birbeck颗粒与中央片层遇到了一个高频率的细胞配置文件。细胞显示吞噬活性。响应于CD 40配体和TNF-α，细胞获得树突状细胞的成熟表型，其特征在于HLA-ABC、HLA-DR、CD 80、CD 86、CD 40和CD 54的上调以及CD 83的出现。这些细胞引起CD 8 ^+ T细胞的活化和CD 4 ^+ T细胞的Th 1极化。因此，在暴露于Notch配体Delta-1、GM-CSF和TGF-β1后，人血液单核细胞可被指示分化成朗格汉斯细胞，这可能部分与人表皮朗格汉斯细胞的发育相关。我们的研究结果不仅扩展了Notch配体Delta-1在人类造血中的功能范围，而且为Langerhans细胞应用于恶性血液病（如多发性骨髓瘤）的细胞免疫治疗提供了可能性。少

IL-6 is widely recognized as a major cytokine that stimulates the proliferation of myeloma cells through paracrine and autocrine mechanisms. We previously reported that IL-6 inhibits the differentiation of human blood monocytes into dermal dendritic cells. It is possible that IL-6 produced by myeloma cells is at least in part involved in the immune deficiency in patients with multiple myeloma. Our objective when we began this study was to restore the immune deficiency associated with multiple myeloma through anti-IL-6 signals. During the study, we incidentally found that the immobilized Notch ligand Delta-1 plays a crucial role in the differentiation of human blood monocytes into Langerhans cells. Recently, it was reported that Notch ligand Delta-1 is expressed in a proportion of the skin. GM-CSF and TGF-β1 are also secreted in the skin. We report here that Notch ligand Delta-1, in concert with GM-CSF and TGF-β1, induces the differentiation of human CD14^+ blood monocytes into cells th … More at express Langerhans cell markers : CD1a, Langerin, cutaneous lymphocyte-associated antigen, CC chemokine receptor 6, and E-cadherin. By transmission electron microscopy, the cells exhibited long prominent dendrites homogenously distributed on the cell surface and contained multiple organelles. Rod-or racket-shaped Birbeck granules with central lamella were encountered at a high frequency in the cell profiles. The cells display the phagocytic activity. In response to CD40 ligand and TNF-α, the cells acquire a mature phenotype of dendritic cells that is characterized by upregulation of HLA-ABC,HLA-DR,CD80,CD86,CD40,and CD54, and appearance of CD83. These cells elicit activation of CD8^+ T cells and Th1 polarization of CD4^+ T cells. Thus, human blood monocytes can be instructed to differentiate into Langerhans cells upon exposure to Notch ligand Delta-1,GM-CSF,and TGF-β1,which may be in part relevant to the development of human epidermal Langerhans cells. Our results not only extend the functional scope of Notch ligand Delta-1 in human hematopoiesis but also provide with the possibility to apply Langerhans cells to cellular immunotherapy for hematological malignancies such as multiple myeloma. Less