Nitric Oxide Regulates Immune Cell Bioenergetic: A Mechanism to Understand Immunomodulatory Functions of Nitric Oxide-Releasing Anti-Inflammatory Drugs

• Published in: The Journal of immunology (1950) 2004-07, Vol.173 (2), p.874-882
• Main Authors: Fiorucci, Stefano, Mencarelli, Andrea, Distrutti, Eleonora, Baldoni, Monia, del Soldato, Piero, Morelli, Antonio
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - physiology; Adjuvants, Immunologic - pharmacology; Anti-Inflammatory Agents - pharmacology; Aspirin - analogs & derivatives; Aspirin - pharmacology; Energy Metabolism - drug effects; Energy Metabolism - physiology; Glycolysis - drug effects; Humans; Mitochondria - drug effects; Mitochondria - physiology; Nitric Oxide - physiology; T-Lymphocytes - drug effects; Triazenes - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.173.2.874

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.