title: N-Octanoyl dopamine transiently inhibits T cell proliferation via G1 cell-cycle arrest and inhibition of redox-dependent transcription factors.
abstract: Recently, we developed a nonhemodynamic dopamine derivative, NOD, which has profound anti-inflammatory effects in vitro. As NOD also protects rats from ischemic AKI, the present study tested whether NOD is able to modulate cellular immunity for potential use as a T cell-suppressive agent. To this end, T cells were stimulated by anti-CD3/CD28 or PMA/ionomycin in the presence or absence of different concentrations of NOD. T cell proliferation, activation markers, intracellular cytokine expression, and activation of transcription factors were assessed. Whereas T cell proliferation was inhibited significantly by NOD at Day 3, proliferation was restored at Day 7 or later depending on the NOD concentration used. Inhibition of proliferation was reflected by a diminished CD25 expression and switch from naive to memory T cells. Early TCR activation events were unaffected, yet NF-κB and AP-1 were strongly inhibited by NOD. The inhibitory effect of NOD seemed to be dependent on its redox activity, as NOT, a redox-inactive NOD derivate, did not influence proliferation. NOD displayed synergistic effects with CNIs on T cell proliferation. Our data demonstrate that NOD displays T cell-suppressive activity. In keeping with its anti-inflammatory action and its beneficial effect on ischemia-induced AKI, NOD may be an interesting drug candidate to prevent CNI-related side-effects.
authors.affiliation: Departments of Medicine, Nephrology, Endocrinology, Diabetology, Rheumatology and.
authors.forename: Johannes
authors.initials: J
authors.lastname: Wedel
authors.affiliation: Anesthesia and Critical Care, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; and.
authors.forename: Maximillia C
authors.initials: MC
authors.lastname: Hottenrott
authors.affiliation: Departments of Medicine, Nephrology, Endocrinology, Diabetology, Rheumatology and.
authors.forename: Eleni
authors.initials: E
authors.lastname: Stamellou
authors.affiliation: Departments of Medicine, Nephrology, Endocrinology, Diabetology, Rheumatology and.
authors.forename: Annette
authors.initials: A
authors.lastname: Breedijk
authors.affiliation: Anesthesia and Critical Care, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; and.
authors.forename: Charalambos
authors.initials: C
authors.lastname: Tsagogiorgas
authors.affiliation: Department of Pathology and Medical Biology, Pathology Section, University of Groningen, University Medical Center, Groningen, The Netherlands.
authors.forename: Jan-Luuk
authors.initials: JL
authors.lastname: Hillebrands
authors.affiliation: Departments of Medicine, Nephrology, Endocrinology, Diabetology, Rheumatology and benito.yard@medma.uni-heidelberg.de.
authors.forename: Benito A
authors.initials: BA
authors.lastname: Yard
mesh_terms: D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D004298:Dopamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D007156:Immunologic Memory; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; C554838:N-octanoyldopamine; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D004298:Dopamine
keywords: AP-1; N-acyl dopamine; NF-κB; T lymphocytes; immunosuppression; transplantation