Perillic acid inhibits Ras/MAP kinase-driven IL-2 production in human T lymphocytes

Perillic acid, a major metabolite of d-limonene, substantially suppressed interleukin-2 (IL-2) and IL-10 production in mitogen-activated T lymphocytes. The effects of perillic acid on cytokine secretion were selective: IL-6 and transforming growth factor-beta 1 (TGF-beta 1) generation were unchanged. In H9 T lymphoma cells, exposure to perillic acid resulted in a dose-dependent depletion of membrane-bound Ras proteins. Unlike hydroxymethyl-glutaryl-CoA reductase or protein farnesyltransferase inhibitors, perillic acid did not induce a shift of membrane-bound into cytosolic p21ras but depleted total cellular Ras proteins. Triggering of the T cell receptor (TCR) perturbs the guanine nucleotide binding cycle of p21ras and in turn induces phosphorylation and activation of mitogen-activated protein kinases (MAPK). In perillic acid-treated cells, the levels of phosphorylated but not total MAPK were also decreased in a dose-dependent manner. Taken together, we provide evidence that perillic acid interrupts signalling via the Ras/MAP kinase pathway by depleting farnesylated Ras levels, an effect which may contribute to its inhibition of IL-2 production and T cell activation.