Abstract
Cucurbitacin R is known to exhibit an anti-inflammatory effect in different experimental models of inflammation. In this article, we outline the effect of cucurbitacin R on T lymphocyte proliferation, cytokine production, and nuclear factor activation, as well as its influence on various experimental models of delayed-type hypersensitivity (DTH) in mice. Cucurbitacin R reduced the proliferation of phytohemagglutinin A-stimulated human T lymphocytes (IC50, 18 μM), modifying the cell cycle, as well as the production of cytokines [interleukin (IL)-2, IL-4, IL-10, and especially interferon-γ] and the induction of the principal cyclins implicated in the cell cycle (A1, B1, D2, and E). These effects are brought on by a novel, selective inhibition of nuclear factor AT (NFAT) by cucurbitacin R, with no concomitant effect on other transcription factors such as activator protein-1. In addition, we tested the in vivo effects of cucurbitacin R in three experimental models of DTH, as well as its effects on T lymphocyte proliferation, the cell cycle, cytokines, and cyclins. Although cucurbitacin R was found to reduce the inflammatory response brought on by both oxazolone and dinitrofluorobenzene, its activity was even more pronounced against sheep red blood cell-induced edema in mouse paws, with a clear reduction in the production of IL-1β, IL-4, and tumor necrosis factor α in the inflamed paw. In conclusion, cucurbitacin R has the potential to be a new immunosuppressive agent with antiproliferative effects through the inhibition of the NFAT with anti-inflammatory activity in DTH reactions.
Footnotes
This work was supported in part by the Spanish government through the Ministerio de Educación y Ciencia [Grant SAF2006-06726]; the Fondo Europeo de Desarrollo Regional (FEDER); and the Generalitat Valenciana [Grant CTBPRB/2003/315].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.159327
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ABBREVIATIONS:
- DTH
- delayed-type hypersensitivity
- DNFB
- dinitrofluorobenzene
- SRBC
- sheep red blood cell
- TNF-α
- tumor necrosis factor α
- IL
- interleukin
- STAT3
- signal transducer and activator of transcription 3
- NF-κB
- nuclear factor κB
- NFAT
- nuclear factor AT
- ELISA
- enzyme-linked immunosorbent assay
- PCR
- polymerase chain reaction
- DAPI
- 6,4′-diamidino-2-phenylindole dihydrochloride
- TPA
- 12-O-tetradecanoylphorbol 13-acetate
- EMSA
- electrophoretic mobility shift assay
- AP-1
- activator protein-1.
- Received July 29, 2009.
- Accepted October 21, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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