Aggregated ursolic acid, a natural triterpenoid, induces IL-1β release from murine peritoneal macrophages:: Role of CD36
Aggregated ursolic acid, a natural triterpenoid, induces IL-1β release from murine peritoneal macrophages:: Role of CD36
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DOI：
10.4049/jimmunol.178.8.4854
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发表时间：
2007-04-15
影响因子：
4.4
通讯作者：
Ohigashi, Hajime
中科院分区：
文献类型：
--
作者：
Ikeda, Yasutaka;Murakami, Akira;Ohigashi, Hajime
IL-1β已被证明在炎症性疾病的发展中起着关键作用。我们最近发现，一种天然的三萜--熊果酸(UA)能促进未受刺激的巨噬细胞释放MIF。在这项研究中，我们研究了尿酸对常驻小鼠腹膜巨噬细胞(PmPhi)产生几种细胞因子的影响。UA以剂量和时间依赖的方式促进IL-1β、IL-6和MIF的蛋白释放，但不增加TNF-α的蛋白释放。该三萜还可显著诱导p38MAPK和ERK1/2的激活以及上游激酶的激活。P38MAPK、MEK1/2、ATP结合盒转运体和caspase-1的抑制剂显著抑制UA诱导的IL-1β的释放。此外，UA诱导细胞内ROS产生IL-1β，该作用可被抗氧化剂抑制。抗CD36单抗可显著抑制IL-1β的释放，表面等离子共振分析结果显示UA与巨噬细胞上的CD36结合。此外，CD36基因缺陷小鼠经UA处理的PmPhi释放的IL-1β量明显低于野生型小鼠。有趣的是，UA被发现聚集在培养上清液中，这些聚集被认为是产生IL-1β的原因。此外，IP。UA可增加ICR小鼠结肠黏膜IL-1β分泌水平和MPO活性。综上所述，我们的结果表明，聚集的UA部分地被巨噬细胞上的CD36识别，从而产生ROS，从而激活p38MAPK、ERK1/2和caspase-1，以及通过ATP结合盒转运蛋白释放IL-1β蛋白。
IL-1 beta has been shown to play a pivotal role in the development of inflammatory disorders. We recently found that a natural triterpene, ursolic acid (UA), enhanced MIF release from nonstimulated macrophages. In this study, we examined the effects of UA on the production of several cytokines in resident murine peritoneal macrophages (pM phi). UA increased the protein release of IL-1 beta, IL-6, and MIF, but not of TNF-alpha, in dose- and time-dependent manners. This triterpene also strikingly induced the activation of p38 MAPK and ERK1/2 together with that of upstream kinases. The release of UA-induced IL-1 beta was significantly inhibited by the inhibitors of p38 MAPK, MEK1/2, ATP-binding cassette transporter, and caspase-1. Furthermore, UA induced intracellular ROS generation for IL-1 beta production, which was suppressed by an antioxidant. Pretreatment with an anti-CD36 Ab significantly suppressed IL-1 beta release, and surface plasmon resonance assay results showed that UA bound to CD36 on macrophages. In addition, the amount of IL-1 beta released from UA-treated pM phi of CD36-deficient mice was markedly lower than that from those of wild-type mice. Interestingly, UA was found to aggregate in culture medium, and the aggregates were suggested to be responsible for IL-1 beta production. In addition, i.p. administration of UA increased the levels of IL-1 beta secretion and MPO activity in colonic mucosa of ICR mice. Taken together, our results indicate that aggregated UA is recognized, in part, by CD36 on macrophages for generating ROS, thereby activating p38 MAPK, ERK1/2, and caspase-1, as well as releasing IL-1 beta protein via the ATP-binding cassette transporter.