Carvacrol and Eugenol Differentially Stimulate Intracellular Ca²⁺ Mobilization and Mitogen-Activated Protein Kinases in Jurkat T-Cells and Monocytic THP-1 Cells

Abstract

Essential oils are a major active constituent found in many Chinese medicinal herbs. Here, we demonstrate that two components of essential oils, carvacrol and eugenol, dose-dependently trigger intracellular Ca²⁺ mobilization in Jurkat T-cells and THP-1 monocytic cells. Both carvacrol and eugenol are also capable of stimulating the active phosphorylation of the p38 subgroup of mitogen-activated protein kinases (MAPKs) in both cell types. However, carvacrol selectively activated the ERK subgroup in Jurkat T-cells, and stimulated the JNK subgroup in THP-1 monocytic cells. Eugenol treatment was not linked to ERK or JNK activation in either cell type. EC₅₀ values for the induction of Ca²⁺ mobilization and MAPK activation were around 10 - 30 μM for both carvacrol and eugenol. Our results suggest that these essential oil components may act as effective agents to modulate the functions of immuno-responsive cells via different intracellular signaling pathways.

Calcium - carvacrol - eugenol - FLIPR - geraniol - MAPK

References

• 1 He L, Mo H, Hadisusilo S, Qureshi A A, Elson C E. Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo .  J Nutr. 1997;  127 668-74
• 2 Zeytinoglu H, Incesu Z, Baser K HC. Inhibition of DNA synthesis by carvacrol in mouse myoblast cells bearing a human N-RAS oncogene.  Phytomedicine. 2003;  10 292-9
• 3 Chainy G BN, Manna S K, Chaturvedi M M, Aggarwal B B. Anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on NF-κB, AP-1, JNK, MAPKK and apoptosis.  Oncogene. 2000;  19 2943-50
• 4 Morrison D K, Davis R J. Regulation of MAP kinase signaling modules by scaffold proteins in mammals.  Annu Rev Cell Dev Biol. 2003;  19 91-118
• 5 Dong C, Davis R J, Flavell R A. MAP kinases in the immune response.  Annu Rev Immunol. 2002;  20 55-72
• 6 Yu J C, Min Z D, Ip N Y. Melia toosendan regulates PC12 cell differentiation via the activation of protein kinase A and extracellular signal-regulated kinases.  Neurosignals. 2004;  13 248-57
• 7 Liu A MF, Ho M KC, Wong C SS, Chan J HP, Pau A HM, Wong Y H. Gα_16/z chimeras efficiently link a wide range of G protein-coupled receptors to calcium mobilization.  J Biomol Screen. 2003;  8 39-49
• 8 Chan A SL, Wong Y H. Epidermal growth factor differentially augments G_i-mediated stimulation of c-Jun N terminal kinase activity.  Br J Pharmacol. 2004;  142 635-46
• 9 Singer A L, Koretzky G A. Control of T cell function by positive and negative regulators.  Science. 2002;  296 1639-40
• 10 Carnesecchi S, Bradaia A, Fischer B, Coelho D, Scholler-Guinard M, Gosse F, Raul F. Perturbation by geraniol of cell membrane permeability and signal transduction pathways in human colon cancer cells.  J Pharmacol Exp Ther. 2002;  303 711-5
• 11 Proost P, Wuyts A, Van Damme J. Human monocyte chemotactic proteins-2 and -3: structural and functional comparison with MCP-1.  J Leukoc Biol. 1996;  9 67-74
• 12 Behrendt H J, Germann T, Gillen C, Hatt H, Jostock R. Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay.  Br J Pharmacol. 2004;  141 737-45
• 13 Magyar J, Szentandrassy N, Banyasz T, Fulop L, Varro A, Nanasi P P. Effects of terpenoid phenol derivatives on calcium current in canine and human ventricular cardiomyocytes.  Eur J Pharmacol. 2004;  487 29-36
• 14 Nishijima H, Uchida R, Kamayama K, Kawakami N, Ohkubo T, Kitamura K. Mechanisms mediating the vasorelaxing action of eugenol, a pungent oil, on rabbit arterial tissue.  Jpn J Pharmacol. 1999;  79 327-34
• 15 Sensch O, Vierling W, Brandt W, Reiter M. Effects of inhibition of calcium and potassium currents in guinea-pig cardiac contraction: comparison of β-caryophyllene oxide, eugenol, and nifedipine.  Br J Pharmacol. 2000;  131 1089-96
• 16 Carnesecchi S, Schneider Y, Ceraline J, Duranton B, Gosse F, Seiler N, Raul F. Geraniol, a component of plant essential oils, inhibits growth and polyamine biosynthesis in human colon cancer cells.  J Pharmacol Exp Ther. 2001;  298 197-200
• 17 Zheng G Q, Kenney P M, Lam L K. Sesquiterpenes from clove (Eugenia caryophyllata) as potential anticarcinogenic agents.  J Nat Prod. 1992;  55 999-1003
• 18 Visconti R, Gadina M, Chiariello M, Chen E H, Stancato L F, Gutkind J S, O’Shea J J. Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity.  Blood. 2000;  96 1844-52
• 19 Morley S J. Signalling through either the p38 or ERK mitogen-activated protein (MAP) kinase pathway is obligatory for phorbol ester and T cell receptor complex (TCR-CD3)-stimulated phosphorylation of initiation factor (eIF) 4E in Jurkat T cells.  FEBS Lett. 1997;  418 327-32
• 20 Schafer P H, Wang L, Wadsworth S A, Davis J E, Siekierka J J. T cell activation signals up-regulate p38 mitogen-activated protein kinase activity and induce TNF-α production in a manner distinct from LPS activation of monocytes.  J Immunol. 1999;  162 659-68
• 21 Foster G H, Tesh V L. Shiga toxin 1-induced activation of c-Jun NH₂-terminal kinase and p38 in the human monocytic cell line THP-1: possible involvement in the production of TNF-α.  J Leukoc Biol. 2002;  71 107-14
• 22 Utsugi M, Dobashi K, Ishizuka T, Endou K, Hamuro J, Murata Y, Nakazawa T, Mori M. c-Jun N-terminal kinase negatively regulates lipopolysaccharide-induced IL-12 production in human macrophages: role of mitogen-activated protein kinase in glutathione redox regulation of IL-12 production.  J Immunol. 2003;  171 628-35