title: Aggregated ursolic acid, a natural triterpenoid, induces IL-1beta release from murine peritoneal macrophages: role of CD36.
abstract: IL-1beta 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 (pMphi). UA increased the protein release of IL-1beta, 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-1beta 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-1beta production, which was suppressed by an antioxidant. Pretreatment with an anti-CD36 Ab significantly suppressed IL-1beta release, and surface plasmon resonance assay results showed that UA bound to CD36 on macrophages. In addition, the amount of IL-1beta released from UA-treated pMphi 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-1beta production. In addition, i.p. administration of UA increased the levels of IL-1beta 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-1beta protein via the ATP-binding cassette transporter.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tachibana
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.forename: Daisaku
authors.initials: D
authors.lastname: Masuda
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Hirano
authors.forename: Shizuya
authors.initials: S
authors.lastname: Yamashita
authors.forename: Hajime
authors.initials: H
authors.lastname: Ohigashi
mesh_terms: D000818:Animals; D015374:Biosensing Techniques; D018955:CD36 Antigens / Q000502:physiology*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D053583:Interleukin-1beta / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D009195:Peroxidase / Q000378:metabolism; D017382:Reactive Oxygen Species; D014315:Triterpenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology; D000097245:Ursolic Acid
chemical_list: D018955:CD36 Antigens; D048049:Extracellular Signal-Regulated MAP Kinases; D053583:Interleukin-1beta; D015850:Interleukin-6; D019746:Intramolecular Oxidoreductases; D008263:Macrophage Migration-Inhibitory Factors; D009195:Peroxidase; D017382:Reactive Oxygen Species; D014315:Triterpenes; D048051:p38 Mitogen-Activated Protein Kinases; D000097245:Ursolic Acid; C076231:Mif protein, mouse