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

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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