Aggregated ursolic acid, a natural triterpenoid, induces IL-1β release from murine peritoneal macrophages: Role of CD36

IL-1β 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 marine peritoneal macrophages (pMφ). UA increased the protein release of IL-1β, IL-6, and MIF, but not of TNF-α, 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-1β 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-1β production, which was suppressed by an antioxidant. Pretreatment with an anti-CD36 Ab significantly suppressed IL-1β release, and surface plasmon resonance assay results showed that UA bound to CD36 on macrophages. In addition, the amount of IL-1β released from UA-treated pMφ 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-1β production. In addition, i.p. administration of UA increased the levels of IL-1β 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-1β protein via the ATP-binding cassette transporter.