Folimycin (concanamycin A) inhibits LPS-induced nitric oxide production and reduces surface localization of TLR4 in murine macrophages
Folimycin (concanamycin A) inhibits LPS-induced nitric oxide production and reduces surface localization of TLR4 in murine macrophages
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DOI：
10.1177/1753425907087349
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发表时间：
2008-02-01
期刊：
影响因子：
3.2
通讯作者：
Chakravortty, Dipshikha
中科院分区：
文献类型：
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作者：
Eswarappa, Sandeepa M.;Basu, Nirmalya;Chakravortty, Dipshikha
内毒素是革兰氏阴性菌的主要细胞壁成分，通过TLR4、MD-2和CD14组成的受体复合体传递信号。巨噬细胞中的内毒素信号诱导许多促炎分子的产生，包括一氧化氮(NO)。在本研究中，我们证明了大环内酯类抗生素和空泡ATPase(V-ATPase)的特异性抑制剂叶霉素能抑制脂多糖诱导的小鼠巨噬细胞产生NO，但不能抑制肿瘤坏死因子-α的产生。但叶霉素不影响干扰素-γ诱导的NO的产生。叶霉素还可抑制脂多糖诱导的iNOS mRNA和蛋白表达及核因子-kappaB的活化。有趣的是，经博莱霉素处理的细胞表面TLRA分子表达减少，高尔基体扩张。这些发现表明，叶霉素通过抑制V-ATPase，改变高尔基体内pH，进而导致TLR4加工缺陷和表面表达减少，从而降低小鼠巨噬细胞内毒素信号的强度。
Lipopolysaccharide (LPS) is a major cell wall component of Gram-negative bacteria and signals through a receptor complex which consists of TLR4, MD-2 and CD14. LPS signaling in macrophages induces the production of many pro-inflammatory molecules, including nitric oxide (NO). In this study, we have shown that folimycin, a macrolide antibiotic and a specific inhibitor of vacuolar ATPase (V-ATPase), inhibits LPS-induced NO production, but not TNF-alpha alpha production, in murine elicited peritoneal macrophages. However, folimycin did not affect interferon-gamma induced NO production. LPS-induced iNOS mRNA and protein expression and NF-kappa B activation were also inhibited by folimycin. Interestingly, folimycin-treated cells showed reduced surface expression of TLRA molecules and dilated Golgi apparatus. These findings suggest that folimycin, by inhibiting V-ATPases, alters intra-Golgi pH, which in turn causes defective processing and reduced surface expression of TLR4 reducing the strength of LPS signaling in murine macrophages.