碩士 / 國立陽明大學 / 傳統醫藥學研究所 / 94 / α-galactosylceramide (α-GalCer), a bioactive glycolipid originally isolated from marine sponge Agelas mauritianus, was shown to act as an immuno-modulating drug. There are many reports describing the therapeutic potential of α-GalCer in treating autoimmune diseases and cancer. In recent years, immunotherapy, based on specific molecular targets, has become a favorable treatment for diverse diseases. Toll-like receptor 4 (TLR4) is commonly expressed in innate immune cells, especially in macrophages and dendritic cells. TLR4 is considered as a promising molecular target for immune-modulating drugs. Many natural products (including polysaccharides, glycolipids, or glycoproteins) can activate TLR4, and thus induce cytokine expression and immune responses. In addition, some TLR4 agonists have been shown to exhibit anti-cancer potential. Currently, combinatorial chemistry-based methods have been commonly applied to synthesize structurally diverse novel compounds, for identifying potential drugs with low-toxicity and better efficacy. In collaboration with Dr. Chun-Cheng Lin’s laboratory, we recently obtained α-GalCer and its related synthetic compounds OCH and CCL 1-55 (55 compounds modified from α-GalCer using combinatorial chemistry). In this study, we tested whether α-GalCer and its derivatives can stimulate macrophage activation.
Using a NF-κB-based reporter assay in murine macrophage RAW 264.7/Luc-P1 cells, we identified a α-GalCer-derived compound, CCL-34, that strongly stimulated NF-κB activity. CCL34 activated NF-κB in a concentration- dependent manner. CCL34-induced gene expression of cytokine (TNF-α, IL-6, GM-CSF) and iNOS in RAW 264.7 cells was detected by RT-PCR. Furthermore, CCL34-induced cytokine secretion (TNF-α, IL-6 and GM-CSF) in RAW 264.7 cells was further validated by ELISA. Our data also showed that CCL-34 treatment of RAW 264.7 cells stimulated NF-κB and MAPK signaling (ERK, JNK and p38) possibly via TLR4 activation. Furthermore, CCL34-treated macrophage displayed a more differentiated cell morphology and exhibited higher phagocytotic activity.
Our data suggested that CCL-34, an α-GalCer-derived compound, can activate the murine macrophages via TLR4. We also provide evidence that CCL-34 is a promising compound for developing immune-modulating drugs.
| Identifer | oai:union.ndltd.org:TW/094YM005373008 |
| Date | January 2006 |
| Creators | Ling-Chien Hung, 洪菱謙 |
| Contributors | Shu-Ling Fu, 傅淑玲 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 62 |
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