GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovica 29, 10000 Zagreb, Croatia.
Cell Immunol. 2012 Sep;279(1):78-86. doi: 10.1016/j.cellimm.2012.09.007. Epub 2012 Oct 1.
Azithromycin and chloroquine have been shown to exhibit anti-inflammatory activities in a number of cellular systems, but the mechanisms of these activities have still not been clarified unequivocally. Since both drugs are cationic, accumulate in acidic cellular compartments and bind to phospholipids with a consequent increase in lysosomal pH and induce phospholipidosis, we examined the relevance of these common properties to their anti-inflammatory activities. We compared also these effects with effects of concanamycin A, compound which inhibits acidification of lysosomes. All three compounds increased lysosomal pH, accumulation of autophagic vacuoles and ubiquitinated proteins and impaired recycling of TLR4 receptor with consequences in downstream signaling in LPS-stimulated J774A.1 cells. Azithromycin and chloroquine additionally inhibited arachidonic acid release and prostaglandin E2 synthesis. Therefore, impairment of lysosomal functions by azithromycin and chloroquine deregulate TLR4 recycling and signaling and phospholipases activation and lead to anti-inflammatory phenotype in LPS-stimulated J774A.1 cells.
阿奇霉素和氯喹已被证明在许多细胞系统中具有抗炎活性，但这些活性的机制仍未得到明确阐明。由于这两种药物都是阳离子的，在酸性细胞区室中积累，并与磷脂结合，导致溶酶体 pH 升高，并诱导磷脂病，因此我们研究了这些共同特性与抗炎活性的相关性。我们还将这些作用与抑制溶酶体酸化的康纳霉素 A 的作用进行了比较。这三种化合物都增加了溶酶体 pH、自噬小泡和泛素化蛋白的积累，并损害了 LPS 刺激的 J774A.1 细胞中 TLR4 受体的再循环，从而导致下游信号转导受到影响。阿奇霉素和氯喹还抑制花生四烯酸释放和前列腺素 E2 合成。因此，阿奇霉素和氯喹对溶酶体功能的损害会使 TLR4 再循环和信号转导以及磷脂酶的激活失去调节，导致 LPS 刺激的 J774A.1 细胞产生抗炎表型。
