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*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*CALCIUM COMPOUNDS
*CALCIUM, ELEMENTAL
*HYDROGEN PEROXIDE
*NITRIC OXIDE
The Journal of Immunology, 2003, 171: 5188-5197.
Copyright © 2003 by The American Association of Immunologists

T Cell Activation-Induced Mitochondrial Hyperpolarization Is Mediated by Ca2+- and Redox-Dependent Production of Nitric Oxide 1

Gyorgy Nagy*, Agnes Koncz* and Andras Perl2,*,{dagger}

Departments of * Medicine and {dagger} Microbiology and Immunology, State University of New York, College of Medicine, Syracuse, NY 13210

Activation, proliferation, or programmed cell death of T lymphocytes is regulated by the mitochondrial transmembrane potential ({Delta}{psi}m) through controlling ATP synthesis, production of reactive oxygen intermediates (ROI), and release of cell death-inducing factors. Elevation of {Delta}{psi}m or mitochondrial hyperpolarization is an early and reversible event associated with both T cell activation and apoptosis. In the present study, T cell activation signals leading to mitochondrial hyperpolarization were investigated. CD3/CD28 costimulation of human PBL elevated cytoplasmic and mitochondrial Ca2+ levels, ROI production, and NO production, and elicited mitochondrial hyperpolarization. Although T cell activation-induced Ca2+ release, ROI levels, and NO production were diminished by inositol 1,4,5-triphosphate receptor antagonist 2-aminoethoxydiphenyl borane, superoxide dismutase mimic manganese (III) tetrakis (4-benzoic acid) porphyrin chloride, spin trap 5-diisopropoxyphosphoryl-5-methyl-1-pyrroline-N-oxide, and NO chelator carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide, mitochondrial hyperpolarization was selectively inhibited by carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (-85.0 ± 10.0%; p = 0.008) and, to a lesser extent, by 2-aminoethoxydiphenyl borane. Moreover, NO precursor (Z)-1-[2-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate diethylenetriamine elicited NO and ROI production, Ca2+ release, transient ATP depletion, and robust mitochondrial hyperpolarization (3.5 ± 0.8-fold; p = 0.002). Western blot analysis revealed expression of Ca-dependent endothelial NO synthase and neuronal NO synthase isoforms and absence of Ca-independent inducible NO synthase in PBL. CD3/CD28 costimulation or H2O2 elicited severalfold elevations of endothelial NO synthase and neuronal NO synthase expression, as compared with {beta}-actin. H2O2 also led to moderate mitochondrial hyperpolarization; however, Ca2+ influx by ionomycin or Ca2+ release from intracellular stores by thapsigargin alone failed to induce NO synthase expression, NO production, or {Delta}{psi}m elevation. The results suggest that T cell activation-induced mitochondrial hyperpolarization is mediated by ROI- and Ca2+-dependent NO production.




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