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

Rocío Sancho, Antonio Macho, Laureano de La Vega, Marco A. Calzado, Bernd L. Fiebich, Giovanni Appendino, Eduardo Muñoz (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    48 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)2341-2351
    Number of pages11
    JournalJournal of Immunology
    Volume172
    Issue number4
    DOIs
    Publication statusPublished - 15 Feb 2004

    Keywords

    • Adult
    • Arachidonic acids
    • Calcineurin
    • Calcineurin inhibitors
    • Cannabinoid receptor Modulators
    • DNA-binding proteins
    • Dopamine
    • Growth inhibitors
    • Humans
    • Immunosuppressive agents
    • Interleukin-2
    • Jurkat cells
    • Lymphocyte activation
    • MAP kinase kinase 1
    • Mitogen-activated protein kinase kinases
    • Mitogen-activated protein kinases
    • NF-kappa B
    • NFATC transcription factors
    • Nuclear proteins
    • Phosphorylation
    • Promoter regions, Genetic
    • Protein subunits
    • Signal transduction
    • T-lymphocytes
    • Transcription factor AP-1
    • Transcription factor RelA
    • Transcription factors
    • Transcriptional activation
    • Tumor necrosis factor-alpha

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