Inhibition of delayed-type hypersensitivity by Cucurbitacin R through the curbing of lymphocyte proliferation and cytokine expression by means of nuclear factor AT translocation to the nucleus.

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 (IC(50), 18 microM), modifying the cell cycle, as well as the production of cytokines [interleukin (IL)-2, IL-4, IL-10, and especially interferon-gamma] and the induction of the principal cyclins implicated in the cell cycle (A(1), B(1), D(2), 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-1beta, IL-4, and tumor necrosis factor alpha 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.

• Authors: José M Escandell, María-Carmen Recio, Rosa M Giner, Salvador Máñez, Miguel Cerdá-Nicolás, Irmgard Merfort, José-Luis Ríos
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 332 Issue 2 Pg. 352-63 (Feb 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 19846588 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• CAVIN3 protein, human
• Cyclins
• Cytokines
• Intracellular Signaling Peptides and Proteins
• NFATC Transcription Factors
• Triterpenes
• cucurbitacin R
• Oxazolone
• Dinitrofluorobenzene

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology, therapeutic use)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cyclins (metabolism)
• Cytokines (metabolism)
• Dinitrofluorobenzene (pharmacology)
• Drug Hypersensitivity (drug therapy)
• Ear (pathology)
• Female
• Foot (pathology)
• Humans
• Hypersensitivity, Delayed (chemically induced, pathology, prevention & control)
• Intracellular Signaling Peptides and Proteins (drug effects)
• Jurkat Cells
• Mice
• NFATC Transcription Factors (antagonists & inhibitors, metabolism)
• Oxazolone (pharmacology)
• T-Lymphocytes (drug effects, metabolism)
• Triterpenes (pharmacology, therapeutic use)