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Release from Murine Peritoneal Macrophages: Role of CD361
* Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan;
Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka, Japan; and
Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
IL-1
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
). UA increased the protein release of IL-1, IL-6, and MIF, but not of TNF-
, 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 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 production, which was suppressed by an antioxidant. Pretreatment with an anti-CD36 Ab significantly suppressed IL-1 release, and surface plasmon resonance assay results showed that UA bound to CD36 on macrophages. In addition, the amount of IL-1 released from UA-treated pM 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 production. In addition, i.p. administration of UA increased the levels of IL-1 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 protein via the ATP-binding cassette transporter.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor, and Welfare of Japan (to A.M.).
2 Address correspondence and reprint requests to Dr. Hajime Ohigashi, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kitashirakawa Oiwake-tyo, Sakyo-ku, Kyoto 606-8502, Japan. E-mail address: ohigashi{at}kais.kyoto-u.ac.jp
3 Abbreviations used in this paper: MIF, macrophage migration inhibitory factor; ABC, ATP binding cassette transporter; DCFH-DA, 2,7'-dichlorofluorescein diacetate; DPI, diphenyleneiodonium; DSS, dextran sulfate sodium; EDTA, ethylene diamine tetraacetic acid; ICE, IL-1-converting enzyme; iNOS, inducible nitric oxide synthase; MEK, MAPK/ERK kinase; MKK, MAPK kinase; MPO, myeloperoxidase; NAC, N-acetyl-L-cysteine; NOX, NADPH oxidase; oxLDL, oxidized low-density lipoprotein; PKC, protein kinase C; pM, peritoneal macrophage; ROS, reactive oxygen species; SPR, surface plasmon resonance; SR, scavenger receptor; UA, ursolic acid.
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