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: S Schulz, D Reinhold, H Schmidt, S Ansorge, V Höllt
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 241 Issue 3 Pg. 720-5 (Dec 29 1997) ISSN: 0006-291X [Print] United States
• PMID: 9434775 (Publication Type: Journal Article)

Chemical References

• Cyclohexenes
• Cytokines
• Interleukin-2
• Membrane Proteins
• Monoterpenes
• Terpenes
• perillic acid
• Calcium-Calmodulin-Dependent Protein Kinases
• GTP-Binding Proteins
• ras Proteins

Topics

• Calcium-Calmodulin-Dependent Protein Kinases (antagonists & inhibitors, physiology)
• Cyclohexenes
• Cytokines (antagonists & inhibitors, biosynthesis)
• Cytosol (drug effects)
• Enzyme Activation (drug effects)
• GTP-Binding Proteins (antagonists & inhibitors)
• Humans
• Interleukin-2 (antagonists & inhibitors, biosynthesis)
• Lymphocyte Activation (drug effects)
• Membrane Proteins (antagonists & inhibitors)
• Monoterpenes
• Signal Transduction (drug effects)
• T-Lymphocytes (drug effects, enzymology, metabolism)
• Terpenes (pharmacology)
• ras Proteins (antagonists & inhibitors, physiology)