Novel synthetic gluco-disaccharide RSCL-0409-a lipopolysaccharide-induced Toll-like receptor-mediated signalling antagonist
Novel synthetic gluco-disaccharide RSCL-0409-a lipopolysaccharide-induced Toll-like receptor-mediated signalling antagonist
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DOI：
10.1111/j.1742-4658.2010.07589.x
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发表时间：
2010-04-01
期刊：
影响因子：
5.4
通讯作者：
Rajagopal, Vikram
中科院分区：
文献类型：
--
作者：
Kalluri, Mani D.;Datla, Praneel;Rajagopal, Vikram
细胞因子和促炎基因的调节是对抗炎症性疾病的绝对必要条件。本文研究了4-O-氯乙酰基-2，3-二-O-乙酰基-6-O-乙酰丙酸-β-D-吡喃葡萄糖基]-（1-3）-1-O-（对甲氧苯基）-2-脱氧-2-N-三氯乙酰基-4，6-O-亚苄基-alpha-d-吡喃葡萄糖苷（RSCL-0409），一种新型小分子Toll样受体（TLR）信号传导拮抗剂，及其在脂多糖（LPS）刺激的人单核细胞（THP-1）中的作用机制。在THP-1和RAW264.7细胞中，RSCL-0409抑制LPS诱导的肿瘤坏死因子-α（TNF-α）的产生，50%抑制浓度为10.6 μ M，并抑制ICAM-1、考克斯-2和白细胞介素-8的mRNA表达，没有细胞毒性的证据。RSCL-0409还抑制LPS刺激的人外周血单核细胞产生TNF-α。在LPS诱导的炎症的鼠模型中体内获得类似的结果，其中用RSCL-0409预处理导致TNF-α的显著抑制。还值得注意的是，RSCL-0409抑制由TLR 2和-4配体诱导的细胞因子产生，而不是任何其他TLR配体。RSCL-0409可显著抑制LPS诱导的p65核转位。总之，RSCL-0409是一种新型小分子，是碳水化合物衍生的TLR信号传导拮抗剂类别中的第一种，并且肯定是一种有前途的炎症性疾病的治疗剂，其发病机制涉及TLR 2或TLR 4介导的信号传导过程。
The regulation of cytokines and pro-inflammatory genes is an absolute essentiality to combat inflammatory diseases. The present study investigated the effects of 4-O-chloroacetyl-2,3-di-O-acetyl-6-O-levulinoyl-beta-d-glucopyranosyl]-(1-3)-1-O-(p-methoxyphenyl)-2-deoxy-2-N-trichloroacetyl-4,6-O-benzylidene-alpha-d-glucopyranoside (RSCL-0409), a novel small molecule Toll-like receptor (TLR) signalling antagonist, and its mechanism of action in human monocytic (THP-1) cells stimulated with lipopolysaccharide (LPS). In THP-1 and RAW264.7 cells, RSCL-0409 suppressed LPS-induced production of tumour necrosis factor-alpha (TNF-alpha) with a 50% inhibitory concentration of 10.6 mu m and mRNA expression of ICAM-1, Cox-2 and interleukin-8 with no evidence of cytotoxicity. RSCL-0409 also suppressed TNF-alpha production from LPS-stimulated human peripheral blood mononuclear cells. Similar results were obtained in vivo in a murine model of LPS-induced inflammation, where pretreatment with RSCL-0409 resulted in significant inhibition of TNF-alpha. It is also noteworthy that RSCL-0409 suppressed the cytokine production induced by TLR2 and -4 ligands and not for any other TLR ligands. RSCL-0409 significantly inhibited p65 nuclear translocation induced by LPS. In conclusion, RSCL-0409, a novel small molecule, is the first of its kind in the category of carbohydrate-derived TLR signalling antagonists and could definitely be a promising therapeutic agent for inflammatory diseases whose pathogenesis involves TLR2- or TLR4-mediated signalling processes.