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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Arachidonic Acids / physiology*
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Calcineurin / metabolism
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Calcineurin Inhibitors
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Cannabinoid Receptor Modulators / physiology*
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / physiology
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Dopamine / analogs & derivatives*
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Dopamine / physiology*
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Growth Inhibitors / physiology
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Humans
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Immunosuppressive Agents / pharmacology*
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Interleukin-2 / genetics
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Jurkat Cells
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Lymphocyte Activation / drug effects
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / metabolism
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NF-kappa B / physiology
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NFATC Transcription Factors
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Nuclear Proteins*
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Phosphorylation / drug effects
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Promoter Regions, Genetic / drug effects
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Promoter Regions, Genetic / immunology
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Protein Subunits / antagonists & inhibitors
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Protein Subunits / metabolism
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Signal Transduction / drug effects
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Signal Transduction / immunology*
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism
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Transcription Factor AP-1 / antagonists & inhibitors*
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Transcription Factor AP-1 / physiology
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Transcription Factor RelA
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / physiology
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Transcriptional Activation / drug effects
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Transcriptional Activation / immunology
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Tumor Necrosis Factor-alpha / genetics
Substances
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Arachidonic Acids
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Calcineurin Inhibitors
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Cannabinoid Receptor Modulators
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DNA-Binding Proteins
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Growth Inhibitors
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Immunosuppressive Agents
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Interleukin-2
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NF-kappa B
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NFATC Transcription Factors
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Nuclear Proteins
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Protein Subunits
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Transcription Factor AP-1
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Transcription Factor RelA
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Transcription Factors
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Tumor Necrosis Factor-alpha
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arachidonyl dopamine
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N-linoleoyldopamine
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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Calcineurin
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Dopamine