著者

中野 真代 小田 真隆 永浜 政博 山本 博文 今川 洋 櫻井 純 西沢 麦夫 樽井 敬史 渋谷 昌弘 大林 寿美代 玉城 翔太

出版者

天然有機化合物討論会実行委員会

雑誌

天然有機化合物討論会講演要旨集

巻号頁・発行日

vol.54, pp.333-338, 2012

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Vizantine (3) is a synthetic derivative of treharose-6,6-dicorynomycolate (TDCM) which was characterized in 1993 as the cell surface glycolipid of Corynebacterium diphtheriae and shows a variety of significant biological activities for adjuvant development. In vitro, vizantine activates not only the macrophages of mice sera, but also induces the release of MIP-1β, IL-6, IL-8 etc. from human acute monocytic leukemia cell line cells (THP-1 cells). Because almost no TNF-α is induced in vivo, the lethal toxicity to animals was found to be ncredibly low. However, oral administration of vizantine to C57BL/6 mouse (p.o. 100 μg x 7 times) inhibits lung metastasis of B16-BL6 melanoma cells (which are classified in highly metastatic tumor cell). In recent years, structural components of the outer surface membrane of bacteria have attracted considerable attention as lead compounds for adjuvant development. However, a concern of the use of these compounds is that they can over-activate innate immune responses leading to the clinical symptoms of septic shock. Therefore, an important issue is a detailed knowledge of the immunostimulatory mechanism to harness beneficial effects without causing toxicity. Here, to advance the mechanistic studies of vizantine, we have synthesized magnetic beads-attached 4 that maintain immunological activities and can therefore act as a molecular probe. Using a pull-down assay of 4 and the extract of HEK-293T cells transfected with plasmid for TLR4 and MD2, vizantine was found to act as a ligand of the Toll-like receptor 4 (TLR4) and MD2 complex. Furthermore, the macrophage from TLR4 knockout (TLR4 -/-) mice showed decreased response to vizantine, but that from TLR2 knockout (TLR2 -/-) mice did not. Taken together the results suggest that vizantine suppresses the tumor lung metastasis through the activation of macrophages via TLR4/MD2 complex.