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.
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.
Departament de Farmacologia, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Valencia, Spain. riosjl@uv.es.
José M
JM
Escandell
María-Carmen
MC
Recio
Rosa M
RM
Giner
Salvador
S
Máñez
Miguel
M
Cerdá-Nicolás
Irmgard
I
Merfort
José-Luis
JL
Ríos
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D016213:Cyclins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004139:Dinitrofluorobenzene / Q000494:pharmacology; D004342:Drug Hypersensitivity / Q000188:drug therapy*; D004423:Ear / Q000473:pathology; D005260:Female; D005528:Foot / Q000473:pathology; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects; D019169:Jurkat Cells; D051379:Mice; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010081:Oxazolone / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology* / Q000627:therapeutic use
D000893:Anti-Inflammatory Agents; C505360:CAVIN3 protein, human; D016213:Cyclins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D050778:NFATC Transcription Factors; D014315:Triterpenes; C517916:cucurbitacin R; D010081:Oxazolone; D004139:Dinitrofluorobenzene