Immunosuppressive activity of endovanilloids: N-arachidonoyl-dopamine inhibits activation of the NF-kappa B, NFAT, and activator protein 1 signaling pathways

• Published in: The Journal of immunology (1950) 2004-02, Vol.172 (4), p.2341-2351
• Main Authors: Sancho, Rocío, Macho, Antonio, de La Vega, Laureano, Calzado, Marco A, Fiebich, Bernd L, Appendino, Giovanni, Muñoz, Eduardo
• Format: Article
• Language: English
• Subjects: Adult; Arachidonic Acids - physiology; Calcineurin - metabolism; Calcineurin Inhibitors; Cannabinoid Receptor Modulators - physiology; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - physiology; Dopamine - analogs & derivatives; Dopamine - physiology; endocannabinoids; Growth Inhibitors - physiology; Humans; immunosuppression; Immunosuppressive Agents - pharmacology; Interleukin-2 - genetics; Jurkat Cells; Lymphocyte Activation - drug effects; MAP Kinase Kinase 1; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; N -arachidonoyl-dopamine; NF-AT protein; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-kappa B - physiology; NFATC Transcription Factors; Nuclear Proteins; Phosphorylation - drug effects; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - immunology; Protein Subunits - antagonists & inhibitors; Protein Subunits - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; t cells; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Transcription Factor AP-1 - antagonists & inhibitors; Transcription Factor AP-1 - physiology; Transcription Factor RelA; Transcription Factors - antagonists & inhibitors; Transcription Factors - physiology; Transcriptional Activation - drug effects; Transcriptional Activation - immunology; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.172.4.2341

Endogenous N-acyl dopamines such as N-arachidonoyldopamine (NADA) and N-oleoyldopamine have been recently identified as a new class of brain neurotransmitters sharing endocannabinoid and endovanilloid biological activities. As endocannabinoids show immunomodulatory activity, and T cells play a key role in the onset of several diseases that affect the CNS, we have evaluated the immunosuppressive activity of NADA and N-oleoyldopamine in human T cells, discovering that both compounds are potent inhibitors of early and late events in TCR-mediated T cell activation. Moreover, we found that NADA specifically inhibited both IL-2 and TNF-alpha gene transcription in stimulated Jurkat T cells. To further characterize the inhibitory mechanisms of NADA at the transcriptional level, we examined the DNA binding and transcriptional activities of NF-kappaB, NF-AT, and AP-1 transcription factors in Jurkat cells. We found that NADA inhibited NF-kappaB-dependent transcriptional activity without affecting either degradation of the cytoplasmic NF-kappaB inhibitory protein, IkappaBalpha, or DNA binding activity. However, phosphorylation of the p65/RelA subunit was clearly inhibited by NADA in stimulated cells. In addition, NADA inhibited both binding to DNA and the transcriptional activity of NF-AT and AP-1, as expected from the inhibition of NF-AT1 dephosphorylation and c-Jun N-terminal kinase activation in stimulated T cells. Finally, overexpression of a constitutively active form of calcineurin demonstrated that this phosphatase may represent one of the main targets of NADA. These findings provide new mechanistic insights into the anti-inflammatory activities of NADA and highlight their potential to design novel therapeutic strategies to manage inflammatory diseases.