Received for publication April 4, 2007.
Revised May 24, 2007.
Accepted for publication June 8, 2007.

Dihydrocucurbitacin B inhibits delayed-type hypersensitivity reactions by suppressing lymphocyte proliferation

Abstract

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 (SRBC), 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- (TNF-). 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 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 (NF-AT) in human lymphocytes without affecting the calcium influx. Taken together, these results suggest that dihydrocucurbitacin B curbs delayed-type hypersensitivity reactions by inhibiting NF-AT, which, in turn, suppresses the proliferation of the most relevant cells involved in DTH reactions, namely the T cells.

Key words: cyclins, cytokines, delayed-type hypersensitivity, dihydrocucurbitacin B, lymphocyte proliferation, nuclear factor-AT