A Novel Aminosaccharide Compound Blocks Immune Responses by Toll-like Receptors and Nucleotide-binding Domain, Leucine-rich Repeat Proteins
A Novel Aminosaccharide Compound Blocks Immune Responses by Toll-like Receptors and Nucleotide-binding Domain, Leucine-rich Repeat Proteins
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DOI：
10.1074/jbc.m110.108001
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发表时间：
2011-02-18
影响因子：
4.8
通讯作者：
Kobayashi, Koichi S.
中科院分区：
文献类型：
--
作者：
Lee, Kyoung-Hee;Liu, Yuen-Joyce;Kobayashi, Koichi S.
Toll样受体（TLR）和核苷酸结合结构域、富含亮氨酸重复序列（NLR）蛋白是两种主要形式的先天性免疫受体，其通过多种生物学机制如细胞因子产生、炎性细胞募集或适应性免疫激活来触发炎症反应。虽然先天免疫系统旨在对抗感染性病原体，但TLR或NLR信号通路的过度激活可能导致不必要的炎症，并产生危险结果，包括感染性休克或炎性疾病。作为寻找有效治疗方法来调节这些反应的一部分，在这里，我们展示了一种名为DFK 1012的新型氨基糖化合物，可以抑制TLR和NLR激活引起的免疫反应。用DFK 1012而不是其衍生物DFK 845或DFK 846处理强烈抑制巨噬细胞中通过TLR或NLR蛋白刺激后的促炎细胞因子产生。重要的是，我们在其工作浓度的任何范围内均未观察到细胞毒性。DFK 1012处理不干扰TLR或NLR诱导的p38和JNK活化、I κ B的磷酸化/降解以及随后NF-κ B亚基p65的核转位，表明DFK 1012的抑制活性不是由于下游信号传导的抑制。事实上，DFK 1012不损害促炎细胞因子基因的转录，而是促进促炎细胞因子的翻译后降解。因此，DFK 1012是一种新型抗炎化合物，其驱动TLR和NLR刺激诱导的促炎细胞因子的蛋白水解。DFK 1012可能代表了一类新的潜在治疗药物，旨在治疗炎症性疾病。
Toll-like receptors (TLRs) and nucleotide-binding domain, leucine-rich repeat (NLR) proteins are two major forms of innate immune receptors that trigger inflammatory responses by various biological mechanisms such as cytokine production, recruitment of inflammatory cells, or activation of adaptive immunity. Although the innate immune system is designed to fight against infectious pathogens, excessive activation of TLR or NLR signaling pathways may lead to unwarranted inflammation with hazardous outcomes, including septic shock or inflammatory diseases. As part of the search for effective therapeutics to regulate these responses, here we show that a novel aminosaccharide compound, named DFK1012, inhibits immune responses caused by TLR and NLR activation. Treatment with DFK1012, but not its derivatives DFK845 or DFK846, strongly inhibited pro-inflammatory cytokine production upon stimulation via either TLR or NLR proteins in macrophages. Importantly, we have not observed cytotoxicity in any range of its working concentration. Treatment with DFK1012 did not interfere with TLR- or NLR-induced activation of p38 and JNK, phosphorylation/degradation of I kappa B, and subsequent nuclear translocation of NF-kappa B subunit p65, suggesting that the inhibitory activity of DFK1012 is not due to the suppression of downstream signaling. Indeed, DFK1012 did not impair transcription of pro-inflammatory cytokine genes but rather promoted post-translational degradation of pro-inflammatory cytokines. Therefore, DFK1012 is a novel anti-inflammatory compound that drives proteolysis of proinflammatory cytokines induced by TLR and NLR stimulation. DFK1012 may represent a novel class of potential therapeutic agents aimed at the treatment of inflammatory disorders.