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Suppression of Interleukin-2 Expression by Arachidonylethanolamide is Mediated by Down-regulation of NF-AT  

Lee, Jung-Hee (Department of Biochemistry, College of Medicine, Inje University)
Park, Kyung-Ran (Department of Biochemistry, College of Medicine, Inje University)
Yea, Sung-Su (Department of Biochemistry, College of Medicine, Inje University)
Publication Information
Molecular & Cellular Toxicology / v.2, no.4, 2006 , pp. 223-228 More about this Journal
Abstract
Several plant-derived cannabinoids and endogenous ligands for cannabinoid receptors such as 2-arachidonyl-glycerol have been known to inhibit interleukin-2 (IL-2) expression. In the present study, we utilized arachidonylethanolamide (AEA), a putative endogenous ligand for cannabinoid receptors, to determine whether AEA modulated the expression of IL-2. AEA inhibited phorbol 12-myristate 13-acetate (PMA) plus ionomycin (Io)-induced IL-2 protein secretion and mRNA expression in EL-4 mouse T-cells as determined by ELISA and RT-PCR, respectively. To further characterize the inhibitory mechanism of AEA at the transcriptional level, we performed promoter study for IL-2 gene in PMA/Io-stimulated EL-4 cells. AEA decreased the transcriptional activity of the nuclear factor of activated T-cells (NF-AT) as well as the IL-2 promoter activity. These results suggest that AEA suppresses IL-2 expression and that the inhibition is mediated, at least in part, through the down-regulation of NF-AT.
Keywords
Arachidonylethanolamide; Interleukin-2; Nuclear factor of activated T-cells;
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1 Devane, W.A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258, 1946-1949 (1992)   DOI
2 Klein, T.W., Newton, C. & Friedman, H. Resistance to Legionella pneumophila suppressed by the marijuana component, tetrahydrocannabinol. J. Infect. Dis. 169, 1177-1179 (1994)
3 Coffey, R.G. et al. Tetrahydrocannabinol inhibition of macrophage nitric oxide production. Biochem. Pharmacol. 52, 743-751 (1996)   DOI   ScienceOn
4 Cabral, G.A. et al. Anandamide inhibits macrophagemediated killing of tumor necrosis factor-sensitive cells. Life Sci. 56, 2065-2072 (1995)   DOI   ScienceOn
5 Truneh, A., Albert, F., Golstein, P. & Schmitt-Verhulst, A.M. Calcium ionophore plus phorbol ester can substitute for antigen in the induction of cytolytic T lymphocytes from specifically primed precursors. J. Immunol. 135, 2262-2267 (1985)
6 Jain, J., Loh, C. & Rao, A. Transcriptional regulation of the IL-2 gene. Curr. Opin. Immunol. 7, 333-342 (1995)   DOI   ScienceOn
7 Dower, N.A. et al. RasGRP is essential for mouse thymocyte differentiation and TCR signaling. Nat. Immunol. 1, 317-321 (2000)   DOI   ScienceOn
8 Rao, A., Luo, C. & Hogan, P.G. Transcription factors of the NFAT family: regulation and function. Annu. Rev. Immunol. 15, 707-747 (1997)   DOI   ScienceOn
9 Macian, F., Lopez-Rodriguez, C. & Rao, A. Partners in transcription: NF-AT and AP-1. Oncogene 20, 2476-2489 (2001)   DOI
10 Ghosh, S. & Baltimore, D. Activation in vitro of NF-$\kappa$B by phosphorylation of its inhibitor IkB. Nature 344, 678-682 (1990)   DOI   ScienceOn
11 Nakano, H. et al. Differential regulation of IkappaB kinase alpha and beta by two upstream kinases, NFkappaB-inducing kinase and mitogen-activated protein kinase/ERK kinase kinase-1. Proc. Natl. Acad. Sci. U.S.A. 95, 3537-3542 (1998)
12 Dunnett, C.W. A multiple comparison procedure for comparing several treatments with a control. J. Am.Stat. Assoc. 50, 1096-1121 (1955)   DOI
13 Ouyang, Y.L., Azcona-Olivera, J.I. & Pestka, J.J. Effects of trichothecene structure on cytokine secretion and gene expression in murine CD4+ T-cells. Toxicology 104, 187-202 (1995)   DOI   ScienceOn
14 Kaminski, N.E. et al. Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G-protein coupled mechanism. Biochem. Pharmacol. 48, 1899-1908 (1994)
15 Baier, G. The PKC gene module: molecular biosystematics to resolve its T cell functions. Immunol. Rev.192, 64-79 (2003)   DOI   ScienceOn
16 Matsuda, L.A. et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561-564 (1990)   DOI   ScienceOn
17 Yea, S.S. et al. Role of nuclear factor of activated T cells and activator protein-1 in the inhibition of interleukin-2 gene transcription by cannabinol in EL4 Tcells. J. Pharmacol. Exp. Ther. 292, 597-605 (2000)
18 Morahan, P.S. et al. Effects of cannabinoids on host resistance to Listeria monocytogenes and herpes simplex virus. Infect. Immun. 2, 670-674 (1979)
19 Condie, R. et al. Cannabinoid inhibition of adenylate cyclase-mediated signal transduction and interleukin 2 (IL-2) expression in the murine T-cell line, EL4. J. Biol. Chem. 271, 13175-13183 (1996)   DOI   ScienceOn
20 Novak, T.J. et al. Regulatory anatomy of the murine IL-2 gene. Nucleic Acids Res. 18, 4523-4533 (1990)   DOI
21 Guzman, M. Cannabinoids: potential anticancer agents. Nat. Rev. Cancer 3, 745-755 (2003)   DOI   ScienceOn
22 Schwarz, H. et al. Anadamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis. J. Neuroimmunol. 55, 107-115 (1994)   DOI   ScienceOn
23 Kumagai, N., Benedict, S.H., Mills, G.B. & Gelfand, E.W. Requirements for the simultaneous presence of phorbol esters and calcium ionophores in the expression of human T lymphocyte proliferation-related genes. J. Immunol. 139, 1393-1399 (1987)
24 Rockwell, C.E. & Kaminski, N.E. A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes. J.Pharmacol. Exp. Ther. 311, 683-690 (2004)   DOI   ScienceOn
25 Munro, S. et al. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61-65 (1993)   DOI   ScienceOn
26 Smith, K.A. Interleukin-2: inception, impact, and implications. Science 240, 1169-1176 (1988)   DOI
27 Herring, A.C. & Kaminski, N.E. Cannabinol-mediated inhibition of nuclear factor-kappaB, cAMP response element-binding protein, and interleukin-2 secretion by activated thymocytes. J. Pharmacol. Exp.Ther. 291, 1156-1163 (1999)
28 Smith, K.A. T-cell growth factor. Immunol. Rev. 51,337-357 (1980)   DOI