title: Nitric oxide regulates immune cell bioenergetic: a mechanism to understand immunomodulatory functions of nitric oxide-releasing anti-inflammatory drugs.
abstract: The 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester (NCX-4016) is a NO-releasing derivative of aspirin. In this study, we provide evidence that NCX-4016 delivered to PMBC-derived T lymphocytes and monocytes causes a transitory inhibition of cell respiration and approximately 50% reduction of cellular ATP, which translates in a time-reversible inhibition of cell proliferation and IL-2, IL-4, IL-5, and IFN-gamma secretion. Exposure of lymphocytes and monocytes to aspirin, 2-(acetyloxy)benzoic acid 3-(hydroxymethyl)phenyl ester (NCX-4017), a non-NO-releasing analog of NCX-4016, and cyclooxygenase inhibitors, reduced PG formation, but has no effect on cytokine/chemokine release. In contrast, delivering NO with (z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino] diazen-1-ium-1,2 diolate (DETA-NO) reproduced most of the metabolic and anti-cytokine activities of NCX-4016. Scavenging NO with hemoglobin or adding selective substrates of complex II, III, and IV of the mitochondrial respiratory chain reverses NCX-4016' inhibitory activities. Exposure to DETA-NO and NCX-4016 enhances glucose uptake, glycolytic rate, and lactate generation in CD3/CD28-costimulated lymphocytes, while reduced citric acid cycle intermediates. These effects were not reproduced by selective and nonselective cyclooxygenase 2 inhibitors. In summary, we demonstrated that exposure of lymphocytes to NCX-4016 causes a metabolic hypoxia that inhibits lymphocyte reactivity to costimulatory molecules, providing a potential counteregulatory mechanism to control activated immune system.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia, Università degli Studi di Perugia, Perugia, Italy. fiorucci@unipg.it
authors.forename: Stefano
authors.initials: S
authors.lastname: Fiorucci
authors.forename: Andrea
authors.initials: A
authors.lastname: Mencarelli
authors.forename: Eleonora
authors.initials: E
authors.lastname: Distrutti
authors.forename: Monia
authors.initials: M
authors.lastname: Baldoni
authors.forename: Piero
authors.initials: P
authors.lastname: del Soldato
authors.forename: Antonio
authors.initials: A
authors.lastname: Morelli
mesh_terms: D000255:Adenosine Triphosphate / Q000502:physiology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology*; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects; D014226:Triazenes / Q000494:pharmacology
chemical_list: C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D000276:Adjuvants, Immunologic; D000893:Anti-Inflammatory Agents; D014226:Triazenes; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; C102148:nitroaspirin; D001241:Aspirin