| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
We have studies the regulation of the differentiation of human blood monocytes by cytokines. When we began this study, our objective was to explore the relevance of lineage switch of human B cells to macrophages to the pathophysiology of Hodgkin lymphoma. During the study, we incidentally found that human blood monocytes can give rise to Langerhans cells upon exposure to the skin cytokine environment consisting of GM-CSF, TGF-pi, and Notch ligand Delta-1 (Delta-1). These Langerhans cells expressed CD1a, E-cadherin, Langerin, CCR6, and Birbeck garanules, all of which are Langerhans cell markers. The cells displayed phagocytic activity and chemotaxis to MlP-la. In response to CD40 ligand and TNF-a, the cells acquired a mature phenotype. The cells in turn showed chemotaxis toward MIP-3P and elicited activation of T cells. The receptors for GM-CSF and IL-3 share a common (3 subunit that transduces the signals into cells. While GM-CSF is produced by a variety of cells that populate the skin
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, IL-3 is not constitutively synthesized in the skin environment and its cellular source is restricted to activated T cells. As previous studies have demonstrated similar activities of GM-CSF and IL-3 on human blood monocytes, we investigated whether IL-3 can replace GM-CSF to generate Langerhans cells from blood monocytes. When cultured in the presence of IL-3, TGF-pi, and Delta-1, monocytes did not become Langerhans cells. However, the addition of GM-CSF to the culture supplemented with IL-3, TGF-pi, and Delta-1 restored the differentiation of monocytes toward Langerhans cells. These data indicate that GM-CSF is indispensable for the induction of Langerhans cells from monocytes. A microarray analysis revealed that there exsited a small subset of genes whose transcripts were significantly up-regulated in the cells cultured with GM-CSF, TGF-pi, and Delta-1 in comparison to those with IL-3, TGF-pi, and Delta-1 and that the subset included E-cadherin and Langerin which are Langerhans cell markers. These results emphasize the importance of the skin environmental milieu in the development of Langerhans cells from blood monocytes. Less
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