title: Perillic acid inhibits Ras/MAP kinase-driven IL-2 production in human T lymphocytes.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schulz
authors.forename: D
authors.initials: D
authors.lastname: Reinhold
authors.forename: H
authors.initials: H
authors.lastname: Schmidt
authors.forename: S
authors.initials: S
authors.lastname: Ansorge
authors.forename: V
authors.initials: V
authors.lastname: Höllt
mesh_terms: D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D053138:Cyclohexenes; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003600:Cytosol / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D039821:Monoterpenes; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D013729:Terpenes / Q000494:pharmacology*; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D053138:Cyclohexenes; D016207:Cytokines; D007376:Interleukin-2; D008565:Membrane Proteins; D039821:Monoterpenes; D013729:Terpenes; C078706:perillic acid; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D018631:ras Proteins