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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Dihydrocucurbitacin B Inhibits Delayed Type Hypersensitivity Reactions by Suppressing Lymphocyte Proliferation

Departament de Farmacologia, Facultat de Farmàcia, Universitat de València, Burjassot, Spain (J.M.E., M.C.R., S.M., R.M.G., J.-L.R.); and Departament de Patologia, Facultat de Medicina, Universitat de València, València, Spain (M.C.-N., R.G.-B.)

We have studied the effects of dihydrocucurbitacin B, a triterpene isolated from Cayaponia tayuya roots, on different models of delayed type hypersensitivity (DTH) in mice, as well as on T-lymphocyte proliferation and the mediators involved. In experiments with mice, dihydrocucurbitacin B inhibited the inflammatory reactions induced by oxazolone, dinitrofluorobenzene, and sheep red blood cells, reducing both the edema and cell infiltration. Moreover, the analysis of inflamed tissues showed that dihydrocucurbitacin B reduced the presence of the most relevant cytokines implicated in these processes, including interleukin-1, interleukin-4, and tumor necrosis factor-. Dihydrocucurbitacin B was also found to inhibit the proliferation of phytohemagglutinin-stimulated human T lymphocytes (IC₅₀ = 1.48 µM), halting the cell cycle in the G₀ phase. In addition, the triterpene reduced the production of interleukin-2, interleukin-4, interleukin-10, and interferon- in human T lymphocytes, and it hampered the induction of the principal cyclins involved in the cell cycle, including A₁, B₁, D₂, and E₁. Finally, dihydrocucurbitacin B was found to exert a selective inhibition on the nuclear factor of activated T cells (NFAT) in human lymphocytes without affecting the calcium influx. Taken together, these results suggest that dihydrocucurbitacin B curbs DTH reactions by inhibiting NFAT, which in turn suppresses the proliferation of the most relevant cells involved in DTH reactions, namely the T cells.

Address correspondence to: Dr. José Luis Ríos, Departament de Farmacologia, Facultat de Farmàcia, Universitat de València, Av. Vicent Andrés Estellés s/n, 46100 Burjassot, Spain. E-mail: riosjl{at}uv.es